Wikiversity enwikiversity https://en.wikiversity.org/wiki/Wikiversity:Main_Page MediaWiki 1.39.0-wmf.21 first-letter Media Special Talk User User talk Wikiversity Wikiversity talk File File talk MediaWiki MediaWiki talk Template Template talk Help Help talk Category Category talk School School talk Portal Portal talk Topic Topic talk Collection Collection talk Draft Draft talk TimedText TimedText talk Module Module talk Gadget Gadget talk Gadget definition Gadget definition talk 0 2084 2408385 2385417 2022-07-21T07:12:45Z 160.154.245.33 /* External links */ Reproducing Piano Rolls wikitext text/x-wiki [[Image:Pianos keyboard with notes.svg|600px|thumb|center]] == How to read piano music == [[File:Alberto Playing Piano 2.jpg|thumb|right|200px|Here are the two staves. Working memory capacity plays a role in a piano player's ability to sight read a new piece of music while playing the piano. Credit: [[c:User:Alfavero|Alfavero]] @ Wikimedia Commons]] [[w:Piano| Piano]] music generally contains two staves: the treble staff and the bass staff. Notes higher than middle C are usually placed on the treble staff while notes lower than middle C are usually placed on the bass staff. The treble [[wiktionary:clef|clef]] may also be called the G clef. The line that passes through the centre of the swirling part of the Treble Clef is the G line. The G just above Middle C sits on this line. The bass clef may also be called the F clef. The line that passes through the two dots of the Bass Clef is the F line. The F just below Middle C sits on this line. Music notes are either placed in spaces or on lines. Moving from a line note to the very next space note in piano music is the same as moving from one white key to the very next white key on the piano. Moving from one note to the next is called a step. The best approach to figuring out note names is by counting steps after having learned the main landmarks: Middle C, G line, F line, Treble C, and Bass C. According to Wictionary, Treble C and Bass C are one octave above and below middle C, which would find them on space 3 of the treble staff, and space 2 (from the bottom) on the bass staff. {{clear}} == How to play major scales == === C Major === [[Image:C major scale.png|right]] The following are some basic scales to learn for the keyboard. The basic C Major scale is shown to the right as a baseline reference. The letters represent notes of the scale, while numbers represent the suggested fingering for each scale. You can use the following fingering for the notes for the right hand: C D E F G A B C 1 2 3 1 2 3 4 5 # 1 represents the thumb. # 2 the index finger. # 3 the middle finger. # 4 the ring finger. # 5 the little finger (pinky). Notice that the thumb goes under the middle finger as the scale progresses from E to F. For the left hand, you can do C D E F G A B C 5 4 3 2 1 3 2 1 Notice that the middle finger is tucked over the thumb as the scale progresses from G to A. === G Major === Right hand fingering G A B C D E F# G 1 2 3 1 2 3 4 5 Left hand fingering G A B C D E F# G 5 4 3 2 1 3 2 1 === D Major === Right hand fingering D E F# G A B C# D 1 2 3 1 2 3 4 5 Left hand fingering D E F# G A B C# D 5 4 3 2 1 3 2 1 === A Major === Right hand fingering A B C# D E F# G# A 1 2 3 1 2 3 4 5 Left hand fingering A B C# D E F# G# A 5 4 3 2 1 3 2 1 === E Major === Right hand fingering E F# G# A B C# D# E 1 2 3 1 2 3 4 5 Left hand fingering E F# G# A B C# D# E 5 4 3 2 1 3 2 1 Notice that the first five scales utilize the same fingerings. Also notice that these scales use reversed finger positions between the two hands. === B/Cb Major === Right hand fingering B/Cb C#/Db D#/Eb E/Fb F#/Gb G#/Ab A#/Bb B 1 2 3 1 2 3 4 5 Left hand fingering B/Cb C#/Db D#/Eb E/Fb F#/Gb G#/Ab A#/Bb B 4 3 2 1 4 3 2 1 === F#/Gb Major === Right hand fingering F#/Gb G#/Ab A#/Bb B/Cb C#/Db D#/Eb E#/Fb F#/Gb 2 3 4 1 2 3 1 2 Left hand fingering F# G# A# B C# D# E# F# 4 3 2 1 3 2 1 2 === Db/C# Major === Right hand fingering Db/C# Eb/D# F/E# Gb/F# Ab/G# B/A# C/B# Db/C# 2 3 1 2 3 4 1 2 Left hand fingering Db/C# Eb/D# F/E# Gb/F# Ab/G# B/A# C/B# Db/C# 3 2 1 4 3 2 1 2 == Case studies == Here are suggestions for piano studies (listed roughly by difficulty) To participate in these case studies, one should have the music readily available (most of them can be easily found at [http://imslp.org/wiki/ IMSLP]). * Hanon: [http://imslp.org/wiki/The_Virtuoso_Pianist_(Hanon,_Charles-Louis) The Virtuoso Pianist in 60 Exercises] * Short pieces from The Notebook for Anna Magdalena Bach by Johann Sebastian Bach * Nineteenth-Century Pedagogical Character Pieces such as those of Cornelius Gurlitt or Friedrich Burgmuller * School of Velocity and Other Studies by Carl Czerny. * Mikrokosmos of Bela Bartok * Tewntieth-Century Character pieces such as those of Dimitri Kabalevsky, Alexander Gretchaninoff or Samuel Maykapar * Two- and Three-Part Inventions of Johann Sebastian Bach * Multi-movement sonatinas such as those of Muzio Clementi * More difficult Nineteenth-Century Character Pieces such as those of Robert Schumann, Edvard Grieg or Felix Mendelssohn * More Complex Sonata forms such as those of Franz Josef Haydn or Wolfgang Amadeus Mozart * Nocturnes of Frederic Chopin * "Pictures at an Exhibition" by Mussorgsky * Preludes and Fugues of Johann Sebastian Bach's Well-Tempered Clavier * Sonatas of Ludwig van Beethoven * Etudes by Frederic Chopin * Etudes-Tableaux by Sergei Rachmaninoff * Douze Études d'exécution transcendante by Franz Liszt * Other works by Liszt, Rachmaninoff and Chopin Beginner pianists should not be daunted by the size of the list, especially its latter half; working through these studies should take months if not years of devoted practice. Take note that the above list consists only of suggestions, and are not "mandatory for any and all pianists." However, in the process of studying a piece, a pianist ought not to put emphasis on snapping up the piece as quickly as possible; rather, he should take time ensure that the technique is being properly developed. It is difficult to correct technical errors once they have been practiced solidly into a piece. ==Technique== [[File:Mikhail Shehtman (hands playing a piano).jpg|thumb|right|200px|Here are fingers in motion. Credit: Quincena Musical @ Flickr]] To achieve a perfect technique and total virtuoso piano playing, one must consider several critical factors, these must be reviewed and taken into account at all times. * One of the most important is to have a position of the hands as relaxed as possible, without any unnecessary tension at the wrists and the rest of the hand. * Another factor to be taken into account is that when we play there must be a connection between the fingers, just at the time one of the fingers rises, the other lowers. In other words: there should never be a silence (no matter how minimal) between the two notes, nor should the notes sound simultaneously (even in a lapse of microseconds). * Another factor that is important is the position of the hands, which should always be light and playing with the pads of the fingers (not fingertips). * Another point that should be taken into account is that the speed of your fingers has to be equal. Normally, there are many mediocre pianists whose fingers 2 and 3 have much more strength and speed than those 4 and 5. This must be avoided. At this particular point, Hanon helps a lot, enlisted in the works above. {{clear}} ==See also== This page was requested at [[Wikiversity:Requests]] You may want to get involved at [[Basic Blues & Rock]] or [[Jazz]] if you are interested in playing piano, organ or keyboards within those [[w:Music genres|Music genres]]. [[Commons:Musical_notation | Musical Notation Article]] ==External links== *[https://commons.wikimedia.org/w/index.php?title=Category:Piano_rolls&diff=649461273&oldid=649461133 Reproducing Piano Rolls] *[http://www.ibiblio.org/mutopia/ Mutopia], an online resource for free sheet music *[http://www.imslp.org/ IMSLP], International Music Score Library Project, a resource containing many music scores, including some of the ones recommended in the article *[http://www.pianofundamentals.com/ Fundamentals of Piano Practice], online textbook teaching the most efficient way to practice piano playing *Useful links for "[http://www.mutopiaproject.org/cgibin/piece-info.cgi?id=781 Wedding-day at Troldhaugen]" by [[w:Lyric Pieces|Edvard Grieg]]. *[http://www.learnmusik.com Piano lessons in London], List of piano teachers in London and the UK *[http://www.gsokol.com Pianist, composer, and piano teacher in London], private piano teacher based in central London *Listen to some classical piano recordings from a [http://nieldupreez.eu pianist in London] {{Musical instruments}} [[Category:Music instruments]] njf8lesyq36lumsojipzkfxydorw6a2 0 3858 2408298 2405643 2022-07-21T05:26:18Z Buckminsterfullrene 2945188 /* Chennai */ wikitext text/x-wiki [[Image:Sage (Leucophyllum?).png|thumb|right|[[w:Sage|Sage]]]] Instructions: Sign up under country, state/province, county, and town (the latter encouraged but not required for those with privacy concerns) to allow for interpretaion of your bloom time data. In order to make the data easier for bots to go through, use alternate accounts if you are recording from different regions. '''Note:''' Contributors who are logging bloom times from more than one geographical area should use alternate accounts, in order to make it easy to analyze the data. ==Austria== ===Styria=== ====Gleisdorf==== --[[User:Anna gdf|Anna gdf]] 11:19, 11 May 2010 (UTC) :*Latitude 47° 06' N :*Longitude 15° 42' O ===Vienna=== *--[[User:Anna reg|Anna reg]] 11:32, 12 April 2010 (UTC) :*Latitude 48° 12′ N :*Longitude 16° 22′ O ==Australia== ===New South Wales=== *-- [[User:Callicoma|Callicoma]] Annandale 31 January 2011 :*Latitude 33.8814° S :*Longitude ; 151.1707° E *_ [[User:Gavman2508|Gavman2508]] Newcastle 26 December 2011 :*32° 55′ 0″ S, 151° 45′ 0″ E ===Victoria=== *-- [[User:MichaelBillington|Michael Billington]] ([[User talk:MichaelBillington|talk]] • [[Special:Contributions/MichaelBillington|contribs]]) :*Latitude 37°49′52″S :*Longitude 145°21′36″E *--[[User:HortMan|HortMan]] 11:30, 1 April 2008 (UTC) :*Melbourne ===Western Australia=== *-- [[User:Gnangarra|Gnangarra]] - All new entries to confirmed with photographic evidence loaded onto commons :*Latitude 31°52′48″S :*Longitude 115°52′58″E ==Canada== ===Ontario=== *--[[User:Kember|Kember]] :*Latitude 46º 34' N :*Longitude 80º 09' W *[[User:Khono|Khono]] 04:34, 17 February 2009 (UTC) :*Newmarket, Ontario :*Latitude 44º 03' N :*Longitude 79º 27' W ====Toronto==== *[[User:Historybuff|Historybuff]] 14:21, 9 May 2007 (UTC) *--[[User:Rene|Rene]] 18:10, 17 Feb 2009 (UTC) :*Latitude 43º 40' N :*Longitude 79º 24' W ===Winnipeg=== *--[[User:Wolf1989|Wolf1989]] :*Latitude 49° 53' N :*Longitude 97° 10' W ===Québec=== *--[[User:L'Assomption|L'Assomption]] :*Latitude 45º 50' N :*Longitude 73º25' W ===British Columbia=== *--[[User:Bridget barcode|Bridget barcode]] :*Latitude 49* 10' N :Longitude 123º 56' W ===Alberta=== *--[[User:racheleverest12|racheleverest12]] :*Latitude 51º 56' N :Longitude 114º 06' W ==Czech Republic== ===Prague=== *--[[User:Juan|Juan]] 14:40, 4 October 2007 (UTC) :*Latitude 50º 5′ 14″ N :*Longitude 14º 25′ 16″ E :*Elevation: 177-399 m :*Weather: :*Morphology: :*Type: urban === Central Bohemian Region === ==== Karlstein ==== *--[[User:Juan Karlstein|Juan Karlstein]] 17:11, 11 October 2007 (UTC) :*Latitude 49° 55′ 56″ N :*Longitude 14° 10′ 31″ E :*Elevation: 210-380 m :*Weather: :*Morphology: :*Type: rural/forest === South Bohemian Region === ==== Pisek District ==== *--[[User:Juan Pisek|Juan Pisek]] 17:26, 11 October 2007 (UTC) :*Latitude :*Longitude :*Elevation: :*Weather: :*Morphology: :*Type: urban/rural/countryside ==== Cesky Krumlov ==== *--[[User:Juan-Cesky Krumlov|Juan-Cesky Krumlov]] 17:56, 11 December 2007 (UTC) :*Latitude :*Longitude :*Elevation: :*Weather: :*Morphology: :*Type: === Western Bohemian Region === ==== Karlovy Vary ==== *--[[User:Juan Karlovy Vary|Juan Karlovy Vary]] 23:01, 23 March 2008 (UTC) :*Latitude :*Longitude :*Elevation: :*Weather: :*Morphology: thermal streams :*Type: urban/urban park === Moravian-Silesian Region === ==== Ostrava ==== * --[[User:Chemgym|Chemgym]] 19:52, 22 April 2008 (UTC) :*Latitude 49° 50′ 8″ N :*Longitude 18° 17′ 33″ E :*Elevation: 260 m :*Weather: local climate is temperate with warm summers and cold, cloudy, humid winters :*Morphology: :*Type: urban == Germany == === Saxony === ==== Leipzig Lowlands ==== *-- [[User:Turnvater Jahn|Turnvater Jahn]] 16:10, 20 May 2008 (UTC) :*Latitude 51°22' N :*Longitude 12°21' E :*Elevation 100 m NN ==== Chemnitz, foothills Ore Mountains ==== *-- [[User:Turnvater Jahn C|Turnvater Jahn C]] 14:35, 5 June 2008 (UTC) :*Latitude 50°50' N :*Longitude 12°55' E :*Elevation 300 m NN == Greece == === Attica === ==== Athens ==== :*Latitude 37°58′ N :*Longitude 23°43′ E *--[[User:Sgv 6618]] 12:20, 18 Mzr 2015 (UTC) == India== === Tamil Nadu === ==== Chennai ==== :*Latitude 13⁰05' N :*Longitude 80⁰18' E *--[[User:ADC]] 10:30, 20 Mar 2008 (UTC) *--[[User:Buckminsterfullrene]] 10:55, 21 Jul 2022 (IST) ==Japan== *--[[User:BrightBoo|Terry]]12:20, 7 Feb 2008 (UTC) === Hokkaido === ===Tohoku=== ===Kanto=== ====Hiratuka==== *--[[User:BrightBoo|Terry]]12:20, 7 Feb 2008 (UTC) :*Latitude 35º21' N :*Longitude 139º 17' E ===Chubu=== ===Kansai=== ===Chyugoku=== ===Shikoku=== ===Kyusyu=== ===Okinawa=== ==Mexico== ===Guanajuato=== *--[[User:Isildil|Isildil]] :*Latitude 21º 07' N :*Longitude 101º 40' O ==New Zealand== ===Auckland=== *--[[User:SortaQuiet|SortaQuiet]] ===Wellington=== ===Horowhenua=== - Levin [[User:Rambla|Rambla]] 10:03, 20 December 2008 (UTC) ==Sweden== ===Stockholm=== *[[User:Dgse87|Dgse87]] 09:35, 11 December 2009 (UTC) :*Latitude 59° 19′ N :*Longitude 18° 3′ E :*Elevation: 11 m :*Type: Urban ==Switzerland== ===Zürich=== *[[User:Richardofoakshire|Richardofoakshire]] 22:40, 5 March 2011 (UTC) ==United Kingdom== ===Aberdeen=== *--[[User:Paulmartin42|Paulmartin42]] 20:06, 17 May 2008 (UTC) ===Devon=== *--[[User:Herbythyme|{{font|color=green|Herby}}]] <b>^{<small><span style="color:#90F">[[User talk:Herbythyme|talk thyme]]</span></small>}</b> - these will probably be from my garden ===London=== *--[[User:Chelodonium|{{font|color=green|'''Chelodonium'''}}]] | ^{[[User talk:Chelodonium|{{font|color=green|talk}}]]} - will input entries from blooms in london and on jaunts arround the UK. **Category series: LONDON ===Manchester=== *[[User:Cormaggio|Cormaggio]] ^{<small>[[User talk:Cormaggio|talk]]</small>} 15:46, 5 November 2007 (UTC) - intend to document flora of Manchester (possibly other locations also) ==United States== ===Alabama=== Marshall County near Arab #[[User:Duiarmia|Duiarmia]] 21:03, 27 May 2008 (UTC) ===Arkansas=== Washington County #[[User:Wilderix|Wilderix]] 15:03, 8 July 2013 (UTC) === California === ==== San Francisco, 2km from the Pacific Ocean ==== #[[User:Bastique|Bastique]] ==== Oakland, hills area, Alameda County ==== #[[User:heidorn|heidorn]] ==== SanDiegoCounty ==== #[[User:ckgarrod|ckgarrod]] SanDiego 32.8nw117.2 ==== Orange County ==== #[[User:tr3ndyBEAR|tr3ndyBEAR]] (added on: 17 February 2021 (UTC)) === Colorado === Aurora, just east of Denver [[User:Ngravagna|Ngravagna]] 17:00, 22 March 2008 (UTC) Southeast Aurora *[[User:Taylorali|Taylorali]] 21:12, 15 April 2008 (UTC) Colorado Springs *[[User:l_d_allan|l_d_allan]] 20:00, 30 July 2013 (UTC) Western Slope, Gunnison National Forest *[[User:Orschstaffer|Orschstaffer]] '''<span class="sig1" style="background-color:#A2ADD0;color:#353839;">''[[w:User:Orschstaffer|O]]''=[[m:User:Orschstaffer|M]]_{''[[User:Orschstaffer|C]]''}^{[[Special:Contributions/Orschstaffer|4]]}</span>''' 21:11, 26 August 2012 (UTC) === Connecticut === Pat, Tolland County === Florida === === Georgia === Pickens County, North Georgia Baraka Photos Union County, North Georgia Georgia Master Naturalists === Louisiana === Grant Parish === Maryland === ===== Howard County ===== '''James_Hade''', Most entries from flora in and around Patapsco Valley State Park, ([[Ellicott City, MD]]). USDA hardiness zone 6b/7a Latitude 39° 16.3446'N === Massachustts === ===== Franklin County ===== *[[User: TristanDolciano]] Deerfield, USDA Zone 5b === Minnesota === ===== Anoka County ===== *[[User:vaericks|Vaericks]] USDA Zone 4a, northern Anoka County ===== Cass County ===== *[[User:Trinity507|Trinity507]] Logs from southern Cass County and the adjacent Crow Wing County (Brainerd Lakes Area). ===== Todd County ===== *[[User: Timothy Micheal King]] Western Todd County === Missouri=== ===== Carter County ===== *[[User:ottenlipsmv|ottenlipsmv]] ===== St. Louis County ===== *[[User:Clarinetguy097|Clarinetguy097]] ([[User talk:Clarinetguy097|discuss]] • [[Special:Contributions/Clarinetguy097|contribs]]) 12:43, 22 July 2017 (UTC) === Nevada === ===== Washoe County ===== *[[User:Jade Knight|The Jade Knight]] 12:39, 19 September 2008 (UTC) ===New York=== =====Kings County (Brooklyn)===== =====Erie County===== [[User:helikophis|helikophis]] =====Washington County===== [[User:Jomegat-UPNY|Jomegat-UPNY]] ===Arizona=== =====Maricopa County===== * [[User:JWSchmidt]] - **[http://www.sunset.com/sunset/Reference/GardenRef/WesternClimateZones.html#NorCal Sunset Western Climate Zone] #13 **34°N 112°W ===Kentucky=== =====Hopkins County===== * [[user:Jomegat-WKY|Jomegat-WKY]] ===Illinois=== [[User:Laleena|Laleena]] 16:07, 8 June 2007 (UTC), Lake County ===North Carolina=== [[User:Frank|Frank]] 12:02, 30 May 2008 (UTC), Wake County ===Ohio=== =====Wood County===== * [[User:Kathryn]] ===Oregon=== =====Jackson County===== * [[User:Hazel]] Sunset Western Climate Zone] #7 **Category series: SWOR =====Washington County===== * [[User:DonDon]] **Category series: NWOR ===Pennsylvania=== =====Berks County===== *--[[User:SB_Johnny|{{font|color=green|'''SB_Johnny'''}}]] | ^{[[User talk:SB_Johnny|{{font|color=green|talk}}]]} - Most entries coming from blooms on my farm ([[w:Bechtelsville, PA|Bechtelsville, PA]]). **USDA hardiness zone: 6a/b **Nearest GDD clock: **Latitude: 40°22′12″N **Category series: [[:Category:Bloom Clock/Southeastern Pennsylvania Categories|SEPA]] =====Chester County===== *[[User:SBJ|SBJ]] --Alternate account for [[User:SB_Johnny]], for records in or near Malvern, Chester County, PA. **Category series: [[:Category:Bloom Clock/Southeastern Pennsylvania Categories|SEPA]] =====Centre County===== *--[[User:Luai lashire|Luai lashire]] - I'll be logging plants from my garden and the country side imediately surrounding State College. **Category series: [[:Category:Bloom Clock/Central Pennsylvania Categories|CTPA]] =====Montgomery County===== *[[User:SB Johnny-LM|SB Johnny-LM]] -- alternate account for [[User:SB_Johnny]], for recording blooms in Lower Merion Township, where I often work. *[[User:Pfthom01|Pfthom01]] **Category series: [[:Category:Bloom Clock/Southeastern Pennsylvania Categories|SEPA]] ===New Hampshire=== *[[User:Jomegat|Jomegat]] - it's a small state, and I tramp around in several counties (but mostly in Merrimack). **Category series: NHAMP *[[User:SB_Johnny-NHAMP|SB_Johnny-NHAMP]] - yet another alternate account for [[User:SB_Johnny|SB_Johnny]], for logging blooms in New Hampshire. *[[User:Jkdt65|Jkdt65]] - Jaffrey, Cheshire county, generally in the vicinity of Old County Rd. ===Rhode Island=== *[[User:Mu301|mikeu]] - Providence **USDA hardiness zone: 6a **41°50'20"N, 71°23'57"W *[[User:RILockGuy]] - Washington County **Based in Kingston, but hike and observe all over state ===South Carolina=== '''Berkeley County''' ====Greenville County==== =====Greer===== *[[User:Nikhilajain]] **USDA Hardiness Zone: 7B ***34°55′49″N 82°13′30″W ****[[User:Nikhilajain|Nikhilajain]] 16:02, 31 May 2008 (UTC) ===Washington=== =====Spokane County===== * [[User:Abee60]] - [http://www.sunset.com/sunset/garden/article/0,20633,845227,00.html Sunset's climate zone] #2 **47°40’ N, 117°10’ W =====Mason County===== *[[User:maidmarian823|maidmarian823]] - Hoodsport ===Wisconsin=== * [[User:Rayc]] - [http://www.sunset.com/sunset/garden/article/0,20633,845264,00.html Sunset's Climate Zone] #41 ** 43.05° N -87.95° W =====Milwaukee County===== * [[User:GrannyGardener]] **USDA Hardiness Zone: 5B **Sunset climate zone: 41 ===Tennessee=== =====Cumberland County===== * [[User:Lzyjo]] - Recording on the Cumberland Plateau at 1,880 feet near I-40 and Catoosa Wildlife Management Area **USDA Hardiness Zone: 6b **Latitude 36° 2′ N, Longitude 18° 53′ W **Elevation: 610 m (1880 ft) **Type: High-density population/forest ===Virginia=== =====Fauquier County===== * [[User:Serotoninskunk]] - Central Piedmont region - Southern Fauquier County and surrounding areas **USDA Hardiness Zone: 7a **Latitude 38.6, Longitude -77.6° **Elevation: 80 m (270 ft) **Type: Rural/Agricultural (nearby rapid suburban growth and pipeline construction) [[Category:Bloom Clock|Contributors]] o0su11dm9fsktcfcm2cm1epi5xvbfvs 0 6197 2408185 2321155 2022-07-20T16:00:54Z 103.199.225.164 /* Exercise 1 */ wikitext text/x-wiki == Hello World! == The first program that most aspiring programmers write is the classic "Hello World" program. The purpose of this program is to display the text "Hello World!" to the user. The "Hello World" example is somewhat famous as it is often the first program presented when introducing a programming language<ref>[http://www.ntecs.de/old-hp/uu9r/lang/html/lang.en.html Examples of programs in different programming languages]</ref>. {{CodeBox|cpp|#include <iostream> using namespace std; int main() { cout << "Hello World!" << endl; cin.get(); return 0; } | langname = C++ | tryiturl = https://tio.run/##HYsxDsMgDAB3v8JNl2Ro1R3UuT/ojIyFLIGJwExV3k7Tjne6o32/JaI5r6KUR2T0Urs1DuUJMLpoQg2F@x6IsVt0AKKGJYiuG3wAEakOQ@9xeXHOFd@15XhZfoY1ZvdPRO@Jbd3O/cTGNpriw8Ex5xc | tryitname = TIO (Try It Online) }} NOTE: The 'return 0;' as shown above, is not a necessary addition to the 'hello world' program. A return value of 0 in main simply signals to the operating system that everything went smoothly. By default, a C++ program will always return 0 if there is no return at the end of main. == Understanding the Code == Before discussing the particulars, it is useful to think of a computer program simultaneously in terms of both its ''structure'' and its ''meaning''. A C++ program is structured in a specific, particular manner. C++ is a language and therefore has a ''grammar'' similar to a spoken language like English. The grammar of computer languages is usually much, much simpler than spoken languages but comes with the disadvantage of having stricter rules. Applying this structure or grammar to the language is what allows the computer to understand the program and what it is supposed to do. The overall program has a structure, but it is also important to understand the purpose of part of that structure. By analogy, a textbook can be split into sections, chapters, paragraphs, sentences, and words (the structure), but it is also necessary to understand the overall meaning of the words, the sentences, and chapters to fully understand the content of the textbook. You can think of this as the ''semantics'' of the program. A line-by-line analysis of the program should give a better idea of both the structure and meaning of the classic "Hello World" program. == A Detailed Explanation of the Code == === #include === <syntaxhighlight lang="cpp">#include <iostream></syntaxhighlight> The hash sign (#) signifies the start of a ''preprocessor command''. The ''include'' command is a specific preprocessor command that effectively copies and pastes the entire text of the file specified between the angle brackets into the source code. In this case the file is "iostream" which is a standard file that should come with the C++ compiler. This file name is short for "input-output streams"; in short, it contains code for displaying and getting text from the user. The include statement allows a programmer to "include" this functionality in the program without having to literally cut and paste it into the source code every time. The iostream file is part of the ''C++ standard library'', which provides a set of useful and commonly used functionality provided with the compiler. The "include" mechanism, however, can be used both for standard code provided by the compiler and for reusable files created by the programmer. === using namespace std === <syntaxhighlight lang="cpp">using namespace std;</syntaxhighlight> C++ supports the concept of namespaces. A namespace is essentially a prefix that is applied to all the names in a certain set. One way to think about namespaces is that they are like toolboxes with different useful tools. The <code>using</code> command tells the compiler to allow all the names in the "std" namespace to be usable without their prefix. The iostream file defines three names used in this program - <code>cout</code>, <code>cin</code>, and <code>endl</code> - which are all defined in the <code>std</code> namespace. "std" is short for "standard" since these names are defined in the [[w:C++_Standard_Library|standard C++ library]] that comes with the compiler. Without <code>using</code> the std namespace, the names would have to include the prefix and be written as <code>std::cout</code>, <code>std::cin</code>, and <code>std::endl</code>. If we continue with the toolbox example, this code would be saying, "Use the <code>cout</code>, <code>cin</code> and <code>endl</code> tools from the <code>std</code> toolbox." Please note that you should either remember the fact that the iostream file uses the 'std' name space or look it up in the documentation for the iostream file because C++ does not make this connection for you explicitly. A slight feeling of annoyance that you are forced to type this connection in every time you wish to write a new C++ program is entirely normal, indeed justified; may we urge you to consider it a small price to pay for avoiding all the tedious work of constantly retyping ''std::free'' in front of things in your program? === int main() === The starting point of all C++ programs is the main function. This function is called by the operating system when your program is executed by the computer. By execution we mean: perform the actions specified by the statements in your program. === cin, cout === <syntaxhighlight lang="cpp"> cout << "Hello, World!" << endl; cin.get(); </syntaxhighlight> The name <code>cout</code> is short for "character output" and <code>cin</code>, correspondingly, is an abbreviation for "character input". In a typical C++ program, most function calls are of the form <code>object.function_name(argument1, argument2)</code>, such as <code>cin.get()</code> in the example above (where <code>cin</code> is the object, <code>get</code> is the function name, and there are no arguments in the argument list). However, symbols such as <code><<</code> can also behave as functions, as illustrated by the use of <code>cout</code> above. This capability is called ''operator overloading'' which will be discussed later on. === { } === A block of code is defined with the { } tokens. { signifies the start of a block of code and } signifies the end. NOTE: The { } tokens have other uses as well. === semicolons === ''Statements'' in C++ must be terminated with a semicolon, just as sentences in English must be terminated with a period. Just as sentences in English can span several lines, so can statements in C++. In fact you can use as many spaces and new lines between the words of a C++ program as you wish to beautify your code just as spaces are used to justify the text printed on the pages of a book. At one point, IBM tried paying its programmers by the number of lines of code they wrote each week. This did not work very well for C programmers who could make one statement span thousands of lines by simply holding down the enter key to insert lots of new lines between the words of their programs. === return === The ''return'' keyword tells the program to return a value to the function that called this function and then to continue execution in the calling function from the point at which this function was called. The type of the value returned by a function must match the type specified in the declaration of the function. Executing the ''return'' keyword in the main function of a program returns a value and the execution control to the operating system component that launched this program, in effect, terminating the execution of this program. == Compiling the code == In order for the computer to execute the code you have written, it needs to first be compiled by a C++ ''compiler''. The compiler translates the textual representation of the program into a form that a computer can execute more efficiently. === What the compiler does === In very broad terms, the compiler is a translator that acts as an intermediary between the programmer and the CPU on the computer. A high-level language like C++ is actually a sort of 'compromise' language between the native language of the CPU (generally referred to as machine language) and the native language of the programmer (say English). Computers do not natively understand human languages, yet for someone to write computer code in the native language of the machine would be too difficult and time consuming. Therefore, the purpose of the computer language itself is to define a mid-point that is closer to how humans think and organize procedures but is still unambiguously translatable to the native machine language. The compiler therefore is reading in the code written by the programmer and translating it into machine language code, that the computer can execute directly. C++ is a ''compiled language'' that is converted to machine language by the compiler. Beginner programmers will likely also come across the notion of ''interpreted languages'' and ''interpreters''. Since this text covers C++, interpreted languages are not covered in detail; however, in brief, an interpreter is like a compiler that converts the program into machine language at the time it is run on the computer rather than in advance as is done with a compiled language. An example of a interpreted language is JavaScript. === Running the compiler === The code needs to be compiled with a compiler to finish the process. What if you don't have one? Well, the good news is, there are several good compilers that are available for free. The GNU Compiler Collection (GCC) has versions available for most systems and does a good job of implementing the ISO C++ standard. The clang compiler has complete support for C++11 and [[FreeBSD]] fully support clang and C++11. However, many people prefer to use an Integrated Development Environment (IDE) which provides a user friendly environment for developing programs. For MacOS X, there is Xcode which uses gcc for compiling C++. For Windows, there is Dev C++ which also uses gcc for compiling C++, Microsoft Visual C++ (and its free Express version), TCLITE, and ports of the GNU Compiler Collection distributed within Cygwin and MinGW. You might also enjoy using [https://www.geany.org/Download/Releases Geany] Each compiler is invoked in a specific way. For example, if you wish to use GCC, type the following into a terminal: <pre> c++ ex.cpp -o example </pre> Replace <kbd>ex.cpp</kbd> with the name of the source file containing the program you wish to compile. The file name you choose must have an extension of either .cpp or .c++ Replace <kbd>example</kbd> with the file name you wish to use to invoke the executable program. If the compiler detects any errors it will write them out at the terminal so that you can take action to fix them by editing your source file. If no errors are detected the compiler will produce an executable program file, in this case called ''example'' in the same directory as the source file. To invoke the compiled program and thus have your computer execute it, enter: <pre> ./example </pre> and observe that your computer performs the actions you specified in your source file. If you wish to use a different compiler, please consult the documentation describing that compiler for the correct way to invoke it. ==Exercises== ====Exercise 1==== Copy the following, then edit it so it compiles correctly and prints "Hello, World!" on the screen <syntaxhighlight lang="cpp"> #include<iosteam> using namespace std; void main() { cout<<"Hello World"; cin.get(); } </syntaxhighlight> ====Exercise 2==== Change the "Hello, World!" example above to display another line. If Spock were doing this exercise, he might add to it so that it would display: <pre> Hello, World! Live long and prosper. </pre> ====Exercise 3==== Supposing you did use a: <syntaxhighlight lang="cpp"> using namespace std; </syntaxhighlight> statement to reduce the amount of typing required, try removing this statement and see if you can still get your program to compile and run without it. Alternatively if you did not use such a statement, try adding it and seeing how many 'std::' prefixes you can remove as a consequence and still have your program compile and run successfully. ==Where To Go Next== {{:C++/Lessons}} ==References== {{reflist}} * [[w:C preprocessor|C Preprocessor]] article at Wikipedia. * [http://cplusplus.happycodings.com/ Cplusplus Sample Codes] * [https://stroustrup.com/bs_faq2.html Bjarne Stroustrup's C++ Style and Technique FAQ] [[Category:Introductions]] [[Category:C++]] 3mca747u3870u0mbzmfiigep5fzzcah 2408186 2408185 2022-07-20T16:01:43Z 103.199.225.164 /* Exercise 1 */ wikitext text/x-wiki == Hello World! == The first program that most aspiring programmers write is the classic "Hello World" program. The purpose of this program is to display the text "Hello World!" to the user. The "Hello World" example is somewhat famous as it is often the first program presented when introducing a programming language<ref>[http://www.ntecs.de/old-hp/uu9r/lang/html/lang.en.html Examples of programs in different programming languages]</ref>. {{CodeBox|cpp|#include <iostream> using namespace std; int main() { cout << "Hello World!" << endl; cin.get(); return 0; } | langname = C++ | tryiturl = https://tio.run/##HYsxDsMgDAB3v8JNl2Ro1R3UuT/ojIyFLIGJwExV3k7Tjne6o32/JaI5r6KUR2T0Urs1DuUJMLpoQg2F@x6IsVt0AKKGJYiuG3wAEakOQ@9xeXHOFd@15XhZfoY1ZvdPRO@Jbd3O/cTGNpriw8Ex5xc | tryitname = TIO (Try It Online) }} NOTE: The 'return 0;' as shown above, is not a necessary addition to the 'hello world' program. A return value of 0 in main simply signals to the operating system that everything went smoothly. By default, a C++ program will always return 0 if there is no return at the end of main. == Understanding the Code == Before discussing the particulars, it is useful to think of a computer program simultaneously in terms of both its ''structure'' and its ''meaning''. A C++ program is structured in a specific, particular manner. C++ is a language and therefore has a ''grammar'' similar to a spoken language like English. The grammar of computer languages is usually much, much simpler than spoken languages but comes with the disadvantage of having stricter rules. Applying this structure or grammar to the language is what allows the computer to understand the program and what it is supposed to do. The overall program has a structure, but it is also important to understand the purpose of part of that structure. By analogy, a textbook can be split into sections, chapters, paragraphs, sentences, and words (the structure), but it is also necessary to understand the overall meaning of the words, the sentences, and chapters to fully understand the content of the textbook. You can think of this as the ''semantics'' of the program. A line-by-line analysis of the program should give a better idea of both the structure and meaning of the classic "Hello World" program. == A Detailed Explanation of the Code == === #include === <syntaxhighlight lang="cpp">#include <iostream></syntaxhighlight> The hash sign (#) signifies the start of a ''preprocessor command''. The ''include'' command is a specific preprocessor command that effectively copies and pastes the entire text of the file specified between the angle brackets into the source code. In this case the file is "iostream" which is a standard file that should come with the C++ compiler. This file name is short for "input-output streams"; in short, it contains code for displaying and getting text from the user. The include statement allows a programmer to "include" this functionality in the program without having to literally cut and paste it into the source code every time. The iostream file is part of the ''C++ standard library'', which provides a set of useful and commonly used functionality provided with the compiler. The "include" mechanism, however, can be used both for standard code provided by the compiler and for reusable files created by the programmer. === using namespace std === <syntaxhighlight lang="cpp">using namespace std;</syntaxhighlight> C++ supports the concept of namespaces. A namespace is essentially a prefix that is applied to all the names in a certain set. One way to think about namespaces is that they are like toolboxes with different useful tools. The <code>using</code> command tells the compiler to allow all the names in the "std" namespace to be usable without their prefix. The iostream file defines three names used in this program - <code>cout</code>, <code>cin</code>, and <code>endl</code> - which are all defined in the <code>std</code> namespace. "std" is short for "standard" since these names are defined in the [[w:C++_Standard_Library|standard C++ library]] that comes with the compiler. Without <code>using</code> the std namespace, the names would have to include the prefix and be written as <code>std::cout</code>, <code>std::cin</code>, and <code>std::endl</code>. If we continue with the toolbox example, this code would be saying, "Use the <code>cout</code>, <code>cin</code> and <code>endl</code> tools from the <code>std</code> toolbox." Please note that you should either remember the fact that the iostream file uses the 'std' name space or look it up in the documentation for the iostream file because C++ does not make this connection for you explicitly. A slight feeling of annoyance that you are forced to type this connection in every time you wish to write a new C++ program is entirely normal, indeed justified; may we urge you to consider it a small price to pay for avoiding all the tedious work of constantly retyping ''std::free'' in front of things in your program? === int main() === The starting point of all C++ programs is the main function. This function is called by the operating system when your program is executed by the computer. By execution we mean: perform the actions specified by the statements in your program. === cin, cout === <syntaxhighlight lang="cpp"> cout << "Hello, World!" << endl; cin.get(); </syntaxhighlight> The name <code>cout</code> is short for "character output" and <code>cin</code>, correspondingly, is an abbreviation for "character input". In a typical C++ program, most function calls are of the form <code>object.function_name(argument1, argument2)</code>, such as <code>cin.get()</code> in the example above (where <code>cin</code> is the object, <code>get</code> is the function name, and there are no arguments in the argument list). However, symbols such as <code><<</code> can also behave as functions, as illustrated by the use of <code>cout</code> above. This capability is called ''operator overloading'' which will be discussed later on. === { } === A block of code is defined with the { } tokens. { signifies the start of a block of code and } signifies the end. NOTE: The { } tokens have other uses as well. === semicolons === ''Statements'' in C++ must be terminated with a semicolon, just as sentences in English must be terminated with a period. Just as sentences in English can span several lines, so can statements in C++. In fact you can use as many spaces and new lines between the words of a C++ program as you wish to beautify your code just as spaces are used to justify the text printed on the pages of a book. At one point, IBM tried paying its programmers by the number of lines of code they wrote each week. This did not work very well for C programmers who could make one statement span thousands of lines by simply holding down the enter key to insert lots of new lines between the words of their programs. === return === The ''return'' keyword tells the program to return a value to the function that called this function and then to continue execution in the calling function from the point at which this function was called. The type of the value returned by a function must match the type specified in the declaration of the function. Executing the ''return'' keyword in the main function of a program returns a value and the execution control to the operating system component that launched this program, in effect, terminating the execution of this program. == Compiling the code == In order for the computer to execute the code you have written, it needs to first be compiled by a C++ ''compiler''. The compiler translates the textual representation of the program into a form that a computer can execute more efficiently. === What the compiler does === In very broad terms, the compiler is a translator that acts as an intermediary between the programmer and the CPU on the computer. A high-level language like C++ is actually a sort of 'compromise' language between the native language of the CPU (generally referred to as machine language) and the native language of the programmer (say English). Computers do not natively understand human languages, yet for someone to write computer code in the native language of the machine would be too difficult and time consuming. Therefore, the purpose of the computer language itself is to define a mid-point that is closer to how humans think and organize procedures but is still unambiguously translatable to the native machine language. The compiler therefore is reading in the code written by the programmer and translating it into machine language code, that the computer can execute directly. C++ is a ''compiled language'' that is converted to machine language by the compiler. Beginner programmers will likely also come across the notion of ''interpreted languages'' and ''interpreters''. Since this text covers C++, interpreted languages are not covered in detail; however, in brief, an interpreter is like a compiler that converts the program into machine language at the time it is run on the computer rather than in advance as is done with a compiled language. An example of a interpreted language is JavaScript. === Running the compiler === The code needs to be compiled with a compiler to finish the process. What if you don't have one? Well, the good news is, there are several good compilers that are available for free. The GNU Compiler Collection (GCC) has versions available for most systems and does a good job of implementing the ISO C++ standard. The clang compiler has complete support for C++11 and [[FreeBSD]] fully support clang and C++11. However, many people prefer to use an Integrated Development Environment (IDE) which provides a user friendly environment for developing programs. For MacOS X, there is Xcode which uses gcc for compiling C++. For Windows, there is Dev C++ which also uses gcc for compiling C++, Microsoft Visual C++ (and its free Express version), TCLITE, and ports of the GNU Compiler Collection distributed within Cygwin and MinGW. You might also enjoy using [https://www.geany.org/Download/Releases Geany] Each compiler is invoked in a specific way. For example, if you wish to use GCC, type the following into a terminal: <pre> c++ ex.cpp -o example </pre> Replace <kbd>ex.cpp</kbd> with the name of the source file containing the program you wish to compile. The file name you choose must have an extension of either .cpp or .c++ Replace <kbd>example</kbd> with the file name you wish to use to invoke the executable program. If the compiler detects any errors it will write them out at the terminal so that you can take action to fix them by editing your source file. If no errors are detected the compiler will produce an executable program file, in this case called ''example'' in the same directory as the source file. To invoke the compiled program and thus have your computer execute it, enter: <pre> ./example </pre> and observe that your computer performs the actions you specified in your source file. If you wish to use a different compiler, please consult the documentation describing that compiler for the correct way to invoke it. ==Exercises== ====Exercise 1==== Copy the following, then edit it so it compiles correctly and prints "Hello, World!" on the screen <syntaxhighlight lang="cpp"> #include<iostream> using namespace std; void main() { cout<<"Hello World"; cin.get(); } </syntaxhighlight> ====Exercise 2==== Change the "Hello, World!" example above to display another line. If Spock were doing this exercise, he might add to it so that it would display: <pre> Hello, World! Live long and prosper. </pre> ====Exercise 3==== Supposing you did use a: <syntaxhighlight lang="cpp"> using namespace std; </syntaxhighlight> statement to reduce the amount of typing required, try removing this statement and see if you can still get your program to compile and run without it. Alternatively if you did not use such a statement, try adding it and seeing how many 'std::' prefixes you can remove as a consequence and still have your program compile and run successfully. ==Where To Go Next== {{:C++/Lessons}} ==References== {{reflist}} * [[w:C preprocessor|C Preprocessor]] article at Wikipedia. * [http://cplusplus.happycodings.com/ Cplusplus Sample Codes] * [https://stroustrup.com/bs_faq2.html Bjarne Stroustrup's C++ Style and Technique FAQ] [[Category:Introductions]] [[Category:C++]] ip9qopb7mi0wbbfblq8xedhvnlt2w6u 0 34381 2408166 2408141 2022-07-20T12:16:10Z JavaHurricane 2886106 Reverted edits by [[Special:Contributions/119.160.69.95|119.160.69.95]] ([[User_talk:119.160.69.95|talk]]) to last version by [[User:Hasley|Hasley]] using [[Wikiversity:Rollback|rollback]] wikitext text/x-wiki {{RoundBoxTop|theme=16}} == Introduction == This course is an introduction for non-computer science students (see [[Introduction_to_Computer_Science|Introduction to Computer Science]] for computer science students). Instead this course is a gentler, lighter survey course without delving too much into technical details. It will also examine computers from the perspective on how they influence society. {{RoundBoxBottom|theme=16}} {{RoundBoxTop|theme=16}} == Prerequisites == Prerequisites are courses it is suggested you understand before you attempt this course. If you're having a hard time understanding the material in this course, make sure you understand these prerequisites first. * There are no prerequisites! (You should be able to follow along no matter how little experience you have in this subject.) {{RoundBoxBottom|theme=16}} {{RoundBoxTop|theme=16}} == Lessons == # {{100Percent}} Introduction #* {{100Percent}} [[Introduction_to_Computers/What is a computer|What is a computer?]] #* {{100Percent}} [[Introduction_to_Computers/History|History of computers]] #* {{100Percent}} [[Introduction_to_Computers/Computer types|Computer types]] #* {{100Percent}} [[Introduction_to_Computers/Hardware and software|Hardware and software]] #* {{100Percent}} [[Introduction_to_Computers/Basic operations|Basic operations]] #* {{100Percent}} [[Introduction_to_Computers/Data sizes and speeds|Data sizes and speeds]] # {{100Percent}} Inside a computer case #* {{100Percent}} [[Introduction_to_Computers/Motherboard|Motherboard]] #* {{100Percent}} [[Introduction_to_Computers/Processor|Processor]] #* {{100Percent}} [[Introduction_to_Computers/Memory|Memory]] #* {{100Percent}} [[Introduction_to_Computers/Disks|Disks]] # {{50Percent}} Peripherals #* {{75Percent}} [[Introduction_to_Computers/Input Devices|Input Devices]] #* {{75Percent}} [[Introduction_to_Computers/Output Devices|Output Devices]] #* {{25Percent}} [[Introduction_to_Computers/Future Peripherals|Future Peripherals]] # {{100Percent}} [[Introduction_to_Computers/System software|System software]] # {{100Percent}} [[Introduction_to_Computers/Application software|Application software]] # {{100Percent}} [[Introduction_to_Computers/Personal|Personal]] # {{100Percent}} [[Introduction_to_Computers/Networks|Networks]] # {{100Percent}} [[Introduction_to_Computers/Security|Security]] # {{100Percent}} [[Introduction_to_Computers/Internet|Internet]] # {{100Percent}} [[Introduction_to_Computers/Development|Development]] # {{100Percent}} [[Introduction_to_Computers/Databases|Databases]] # {{100Percent}} [[Introduction_to_Computers/AI|Artificial intelligence]] {{RoundBoxBottom|theme=16}} {{RoundBoxTop|theme=16}} == What Next? == Once you have completed this course, you have learned enough to take these courses: * [[Computer Skills]] * [[IC3 | Internet and Computing Core Certification (IC³)]] * [[IT Fundamentals]] * [[Introduction to Computer Science]] {{RoundBoxBottom|theme=16}} __NOTOC__ [[Category:Computing]] myyz3dgdhzoczo05pg4xpd89s5fpv71 0 67794 2408392 2236813 2022-07-21T10:26:55Z 188.30.6.59 /* Create and manage documents */ wikitext text/x-wiki {{Software-stub}} [[File:Word 2013 On Windows 8.1.png|320x171px|thumbnail|right|An example of Microsoft Word 2013.]] Microsoft Word is a word processor created by Microsoft. Basically, it allows you to create eye-catching text and documents. Today, these documents are generally saved as a [[Wikipedia:Office Open XML|docx]] file, although they can be saved in other formats. == Lessons == === Create and manage documents === * [[/Create a document/]] * [[/Navigate through a document/]] * [[/Format a document/]] * [[/Customize options and views for documents/]] * [[/Configure documents to print or save/]] * [https://www.youtube.com/watch?v=KBbWBNmumMc Create a template] ==Page breaks and section breaks== Scenario: How to create a single landscape page within a portrait-style document. Answer: Put section breaks above and below the content and whilst on the target content go to page setup and change to landscape format. ==Shortcuts== ''External link'': [http://office.microsoft.com/en-us/word/HP051866641033.aspx Keyboard shortcuts for Word] <div style="column-count:3;-moz-column-count:3;-webkit-column-count:3"> * Ctrl+A: Select entire document * Ctrl+B: Toggle Bold * Ctrl+C: Copy * Ctrl+D: Open font dialogue * Ctrl+E: Centralize Selection * Ctrl+F: Find in the open document * Ctrl+G: Open the 'Go To' dialogue box * Ctrl+H: Open the 'Find and Replace' dialogue box * Ctrl+I: Toggle Italic * Ctrl+J: Justify selection * Ctrl+K: Insert hyperlink * Ctrl+L: Align Left * Ctrl+M: Indent * Ctrl+N: Open New document * Ctrl+O: Open file * Ctrl+P: Print document * Ctrl+R: Align Right * Ctrl+S: Save file * Ctrl+U: Toggle Underlined * Ctrl+V: Paste * Ctrl+W: Close * Ctrl+X: Cut * Ctrl+Y: Redo last action * Ctrl+Z: Undo last action * Ctrl+8 (alphanumeric pad): Lower font size * Ctrl+9 (alphanumeric pad): Raise font size * Ctrl+=: Make subscript * Ctrl+Shift-+: Make superscript * Ctrl+Shift+A: Turn all caps * Ctrl+Shift+B: Switch to Symbol font * Ctrl+Shift+ * Ctrl+Shift+Q: Turn into small caps * Ctrl-Alt-M: Add Comment * Alt+X: Convert to/from Unicode codepoint * Shift+F3: Cycle casing (ALL CAPS/all lowercase/Every First Letter Capitalized) *Ctrl+>: Raise font size *Ctrl+<: Lower font size *Ctrl+Shift+C: Format Painter (Copy) *Ctrl+Shift+V: Format Painter (Paste) *Ctrl+Space: Removes all manual character formatting from a selection </div> ==Styles== * [http://addbalance.com/usersguide/styles.htm Understanding styles in Microsoft Word] ==Features== ===Formats=== Formats are one of the most important features in Microsoft Word. This is because they let you chose what size, colour, font, or weather your text is bold, in italics, or underlined. (See figure 4.1) Format painter copies the '''format''' of text, '''not the actual text'''. (See figure 4.2 - 4.4) ==Table of contents== * [http://www.shaunakelly.com/word/toc/CreateATOC.html How to create a table of contents in Microsoft Word] (Shauna Kelly) ==See also== {{wikipedia|Microsoft Word}} * [[IC3/Word Processing | IC³ Word Processing]] ==External links== * [http://www.microsoft.com/word/ Microsoft Word] * [http://office.microsoft.com/en-us/word/HA100444731033.aspx Open a Word 2007 document in an earlier version of Word] == References == * Lambert, J. (2014). MOS 2013 Study Guide for Microsoft Word. Microsoft. {{ISBN|9780735669253}} {{Reflist}} [[Category:Microsoft Office/Word]] jokzvw5hlpycga29sh1f3sdxnd288v0 2408393 2408392 2022-07-21T10:44:21Z 188.30.6.59 Addition of videos on using and creating templates wikitext text/x-wiki {{Software-stub}} [[File:Word 2013 On Windows 8.1.png|320x171px|thumbnail|right|An example of Microsoft Word 2013.]] Microsoft Word is a word processor created by Microsoft. Basically, it allows you to create eye-catching text and documents. Today, these documents are generally saved as a [[Wikipedia:Office Open XML|docx]] file, although they can be saved in other formats. == Lessons == === Create and manage documents === * [[/Create a document/]] * [[/Navigate through a document/]] * [[/Format a document/]] * [[/Customize options and views for documents/]] * [[/Configure documents to print or save/]] * [https://www.youtube.com/watch?v=KBbWBNmumMc Use a template] * [https://www.youtube.com/watch?v=4k3FTbX7G0M Creating templates in Word 2010] * [https://www.youtube.com/watch?v=3tbtRCIyszg Creating templates in Word 2016] ==Page breaks and section breaks== Scenario: How to create a single landscape page within a portrait-style document. Answer: Put section breaks above and below the content and whilst on the target content go to page setup and change to landscape format. ==Shortcuts== ''External link'': [http://office.microsoft.com/en-us/word/HP051866641033.aspx Keyboard shortcuts for Word] <div style="column-count:3;-moz-column-count:3;-webkit-column-count:3"> * Ctrl+A: Select entire document * Ctrl+B: Toggle Bold * Ctrl+C: Copy * Ctrl+D: Open font dialogue * Ctrl+E: Centralize Selection * Ctrl+F: Find in the open document * Ctrl+G: Open the 'Go To' dialogue box * Ctrl+H: Open the 'Find and Replace' dialogue box * Ctrl+I: Toggle Italic * Ctrl+J: Justify selection * Ctrl+K: Insert hyperlink * Ctrl+L: Align Left * Ctrl+M: Indent * Ctrl+N: Open New document * Ctrl+O: Open file * Ctrl+P: Print document * Ctrl+R: Align Right * Ctrl+S: Save file * Ctrl+U: Toggle Underlined * Ctrl+V: Paste * Ctrl+W: Close * Ctrl+X: Cut * Ctrl+Y: Redo last action * Ctrl+Z: Undo last action * Ctrl+8 (alphanumeric pad): Lower font size * Ctrl+9 (alphanumeric pad): Raise font size * Ctrl+=: Make subscript * Ctrl+Shift-+: Make superscript * Ctrl+Shift+A: Turn all caps * Ctrl+Shift+B: Switch to Symbol font * Ctrl+Shift+ * Ctrl+Shift+Q: Turn into small caps * Ctrl-Alt-M: Add Comment * Alt+X: Convert to/from Unicode codepoint * Shift+F3: Cycle casing (ALL CAPS/all lowercase/Every First Letter Capitalized) *Ctrl+>: Raise font size *Ctrl+<: Lower font size *Ctrl+Shift+C: Format Painter (Copy) *Ctrl+Shift+V: Format Painter (Paste) *Ctrl+Space: Removes all manual character formatting from a selection </div> ==Styles== * [http://addbalance.com/usersguide/styles.htm Understanding styles in Microsoft Word] ==Features== ===Formats=== Formats are one of the most important features in Microsoft Word. This is because they let you chose what size, colour, font, or weather your text is bold, in italics, or underlined. (See figure 4.1) Format painter copies the '''format''' of text, '''not the actual text'''. (See figure 4.2 - 4.4) ==Table of contents== * [http://www.shaunakelly.com/word/toc/CreateATOC.html How to create a table of contents in Microsoft Word] (Shauna Kelly) ==See also== {{wikipedia|Microsoft Word}} * [[IC3/Word Processing | IC³ Word Processing]] ==External links== * [http://www.microsoft.com/word/ Microsoft Word] * [http://office.microsoft.com/en-us/word/HA100444731033.aspx Open a Word 2007 document in an earlier version of Word] == References == * Lambert, J. (2014). MOS 2013 Study Guide for Microsoft Word. Microsoft. {{ISBN|9780735669253}} {{Reflist}} [[Category:Microsoft Office/Word]] n3ku5olvjgpxyvssqotetz2q3hxsr58 2408394 2408393 2022-07-21T11:17:47Z 188.30.6.59 Found better video on creating templates in Word 2016 wikitext text/x-wiki {{Software-stub}} [[File:Word 2013 On Windows 8.1.png|320x171px|thumbnail|right|An example of Microsoft Word 2013.]] Microsoft Word is a word processor created by Microsoft. Basically, it allows you to create eye-catching text and documents. Today, these documents are generally saved as a [[Wikipedia:Office Open XML|docx]] file, although they can be saved in other formats. == Lessons == === Create and manage documents === * [[/Create a document/]] * [[/Navigate through a document/]] * [[/Format a document/]] * [[/Customize options and views for documents/]] * [[/Configure documents to print or save/]] * [https://www.youtube.com/watch?v=KBbWBNmumMc Use a template] * [https://www.youtube.com/watch?v=4k3FTbX7G0M Creating templates in Word 2010] * [https://www.youtube.com/watch?v=qs2HzP9Q9eg Creating templates in Word 2016] ==Page breaks and section breaks== Scenario: How to create a single landscape page within a portrait-style document. Answer: Put section breaks above and below the content and whilst on the target content go to page setup and change to landscape format. ==Shortcuts== ''External link'': [http://office.microsoft.com/en-us/word/HP051866641033.aspx Keyboard shortcuts for Word] <div style="column-count:3;-moz-column-count:3;-webkit-column-count:3"> * Ctrl+A: Select entire document * Ctrl+B: Toggle Bold * Ctrl+C: Copy * Ctrl+D: Open font dialogue * Ctrl+E: Centralize Selection * Ctrl+F: Find in the open document * Ctrl+G: Open the 'Go To' dialogue box * Ctrl+H: Open the 'Find and Replace' dialogue box * Ctrl+I: Toggle Italic * Ctrl+J: Justify selection * Ctrl+K: Insert hyperlink * Ctrl+L: Align Left * Ctrl+M: Indent * Ctrl+N: Open New document * Ctrl+O: Open file * Ctrl+P: Print document * Ctrl+R: Align Right * Ctrl+S: Save file * Ctrl+U: Toggle Underlined * Ctrl+V: Paste * Ctrl+W: Close * Ctrl+X: Cut * Ctrl+Y: Redo last action * Ctrl+Z: Undo last action * Ctrl+8 (alphanumeric pad): Lower font size * Ctrl+9 (alphanumeric pad): Raise font size * Ctrl+=: Make subscript * Ctrl+Shift-+: Make superscript * Ctrl+Shift+A: Turn all caps * Ctrl+Shift+B: Switch to Symbol font * Ctrl+Shift+ * Ctrl+Shift+Q: Turn into small caps * Ctrl-Alt-M: Add Comment * Alt+X: Convert to/from Unicode codepoint * Shift+F3: Cycle casing (ALL CAPS/all lowercase/Every First Letter Capitalized) *Ctrl+>: Raise font size *Ctrl+<: Lower font size *Ctrl+Shift+C: Format Painter (Copy) *Ctrl+Shift+V: Format Painter (Paste) *Ctrl+Space: Removes all manual character formatting from a selection </div> ==Styles== * [http://addbalance.com/usersguide/styles.htm Understanding styles in Microsoft Word] ==Features== ===Formats=== Formats are one of the most important features in Microsoft Word. This is because they let you chose what size, colour, font, or weather your text is bold, in italics, or underlined. (See figure 4.1) Format painter copies the '''format''' of text, '''not the actual text'''. (See figure 4.2 - 4.4) ==Table of contents== * [http://www.shaunakelly.com/word/toc/CreateATOC.html How to create a table of contents in Microsoft Word] (Shauna Kelly) ==See also== {{wikipedia|Microsoft Word}} * [[IC3/Word Processing | IC³ Word Processing]] ==External links== * [http://www.microsoft.com/word/ Microsoft Word] * [http://office.microsoft.com/en-us/word/HA100444731033.aspx Open a Word 2007 document in an earlier version of Word] == References == * Lambert, J. (2014). MOS 2013 Study Guide for Microsoft Word. Microsoft. {{ISBN|9780735669253}} {{Reflist}} [[Category:Microsoft Office/Word]] ckjnctk8cikm5wj5bhe6m0g0dq7qmh8 0 138773 2408179 2408115 2022-07-20T13:49:21Z Dave Braunschweig 426084 Reverted edits by [[Special:Contributions/148.64.7.123|148.64.7.123]] ([[User_talk:148.64.7.123|talk]]) to last version by [[User:Tricia.mtl|Tricia.mtl]] using [[Wikiversity:Rollback|rollback]] wikitext text/x-wiki {{TOCright}} Wireshark is a free and open source packet analyzer used for network troubleshooting and analysis. These activities will show you how to use Wireshark to capture and filter network traffic using a display filter. == Readings == # [https://gitlab.com/wireshark/wireshark/-/wikis/DisplayFilters Wireshark: Display Filters] == Multimedia == # [https://www.youtube.com/watch?v=N-HpD0bUSO4 YouTube: Wireshark 101: Display Filters and Filter Options, HakTip 122] == Preparation == To prepare for this activity: # Start your system Linux or Windows. # Log in if necessary. # [[Wireshark/Install | Install Wireshark]]. == Activity 1 - Capture Network Traffic == To capture network traffic: # [[Wireshark/Start | Start a Wireshark capture]]. # Use [[Ping/Host | ping 8.8.8.8]] to ping an Internet host by IP address. # [[Wireshark/Stop | Stop the Wireshark capture]]. == Activity 2 - Use a Display Filter == To use a display filter: # Type '''ip.addr == 8.8.8.8''' in the Filter box and press '''Enter.''' # Observe that the Packet List Pane is now filtered so that only traffic to (destination) or from (source) IP address 8.8.8.8 is displayed. # Click '''Clear''' on the Filter toolbar to clear the display filter. # Close Wireshark to complete this activity. '''Quit without Saving''' to discard the captured traffic. == References == * [http://www.wireshark.org/docs/wsug_html_chunked/ Wireshark: User's Guide] * [https://gitlab.com/wireshark/wireshark/-/wikis/home Wireshark Wiki] *[http://www.admin-magazine.com/Articles/Wireshark Admin Magazine: Wireshark] [[Category:Wireshark]] [[Category:Activities]] 68nbfu8caojsme0hpinhf8gmlva3d5c 1 159077 2408252 2401553 2022-07-21T01:50:32Z Evolution and evolvability 922352 /* Reference deposits */ Reply wikitext text/x-wiki [[Category:WikiJournal]] {{WikiJournal_discussions}} {{Archive box| [[/Archive 2014–2016|2014–2016]] <br>[[/Archive 2016 naming vote|2016 naming vote]] <br>[[/Archive 2017|2017]] <br>[[/Archive 2018|2018]] <br>[[/Archive 2019|2019]] <br>[[/Archive 2020|2020]] <br>[[/Archive 2021|2021]] <br>[[/Archive 2022|2022]] Discussions may also take place at the <br>'''[https://lists.wikimedia.org/pipermail/wikijournal-en/ public mailing list]'' ([https://lists.wikimedia.org/mailman/listinfo/wikijournal-en Join]) }} {{TOClimit|limit=3}} == Banner links must be accessible on smartphones == On smartphones, the banners are hard to tap/click on, especially the Preprint one. I have difficulty changing the banners' format. [[User:George Ho|George Ho]] ([[User talk:George Ho|discuss]] • [[Special:Contributions/George Ho|contribs]]) 12:31, 29 January 2022 (UTC) == Reference deposits == Hi all! I was taking a look at the [https://www.crossref.org/members/prep/6026 WikiJournal User Group participation report] over on Crossref's site. This is a useful tool for exploring how rich the metadata that WJUG submits to Crossref along with its DOIs is. It looks like there's lots of room for improvement, some of which would be fairly straightforward to accomplish: the License URLs category, for instance, measures how many articles' metadata include a link to the license under which the papers are distributed (either CC-BY 4.0 or CC-BY-SA 4.0 typically, right?). What I wanted to look at right now was the References category, in which WJUG is currently scoring 0%. What this means is that none of the 87 articles registered for DOIs by WJUG with Crossref include the references as part of their metadata. This matters for a few reasons. First, reference linking (i.e., including DOIs in references) is required by Crossref's terms of service, and reference depositing (i.e., submitting metadata with references) is strongly encouraged. Second, the inclusion of references in metadata is how Crossref tracks citations. When you see a journal article's "What Cites This" page, you'll often see a few numbers, frequently a Crossref citation count, a Web of Science citation count, and a Google Scholar citation count. On these pages, you are often able to view which articles are specifically citing the article in question too, and in some cases, publishers may preemptively set up modules that autodisplay the citing articles alongside the article itself. This brings up the third reason to begin depositing references: not only is it good practice for good metadata management's sake itself, but it also has the capability to improve visibility for WikiJournal articles. Consider the ''WJS'' article "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]"; its first reference is the 1907 article "Parrakeets Moulting". If you visit the Taylor & Francis [https://doi.org/10.1071/MU906192f page for "Parrakeets Moulting"], however, you can see in the righthand "Related research" module in the "Cited by" tab that no articles cite this paper. Because references for WJUG articles haven't yet been deposited with Crossref, there's no way to link "Beak and feather disease virus" and "Parrakeets Moulting"; if references ''were'' deposited for this paper, then the ''WJS'' article would eventually appear as a citing article on the "Parrakeets Moulting" page. Thus, reference linking offers readers of the cited article another connection to the citing WikiJournal article, increasing the visibility of WJUG outputs. One final reason to consider depositing references is that doing so will grant WJUG eligibility for Crossref's [https://www.crossref.org/documentation/cited-by/ Cited-by service], which is essentially the tool that allows WJUG the ability to see what research is citing WikiJournal articles. Right now, WJUG can access the ''number'' of citations for each of its journals' articles through Crossref (''[http://data.crossref.org/depositorreport?pubid=J243966 WJM]'', ''[http://data.crossref.org/depositorreport?pubid=J310521 WJS]'', and ''[http://data.crossref.org/depositorreport?pubid=J310522 WJH]'') but can't actually see what those citing articles are. Depositing references will grant eligibility for Cited-by which WJUG can opt to enroll in (free!) and access said lists of citing materials for WikiJournal articles. If depositing references is of interest, the good news is that Crossref has made it pretty easy! References can be deposited manually via the [https://apps.crossref.org/SimpleTextQuery Simple Text Query] tool on Crossref's site. All one needs to do is copy the list of references from a WikiJournal article and paste it into the tool. (Note that for some articles, this will be easy; "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]" has a unified reference list, but other articles like "[[WikiJournal of Humanities/Themes in Maya Angelou's autobiographies|Themes in Maya Angelou's autobiographies]]" have references split between a footnotes and a cited by list and may need to be manually trimmed to remove the repeated "[Author], [date], p. XX" footnotes when submitting.) Simple Text Query then parses the list and connects materials based on their DOIs. Once this is done, the depositor clicks ''Deposit'', enters their email, the Parent DOI (i.e., the DOI of the article for which references are being deposited), and their Crossref depositor credentials. I have been manually going through all articles in all three journals to make sure that all of them have relevant DOIs included in their references. I have completed ''WJS'', am almost done with ''WJH'', and will then start on ''WJM''. Once this is done, I would be happy to either guide someone interested through beginning to deposit references or take over the project myself, at least to work through the 87-article backlog of existing papers. (If someone with depositor access wants to try making a reference deposit, "Beak and feather disease virus" is in good shape and its reflist is ready to be deposited.) In either case, please let me know if this is something WJUG would be interested in pursuing and how I can help. Please let me know if you have any questions. Kindly —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 01:02, 19 June 2022 (UTC) : Okay, all ''WJH'' articles now include all available DOIs. ''WJS'' is left to do. —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 20:23, 19 June 2022 (UTC) ::Thanks Colin for the very informative post and your great work on adding DOIs. I will bring this up at our next monthly meeting. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:31, 20 June 2022 (UTC) :::Great points raised! I've added a step-wise summary process [[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|here]] and we're looking at organising going through and uploading the back-catalogue. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:50, 21 July 2022 (UTC) kvlhmpoqkfnl3p3szxz8wgdsh5cy28o 2408255 2408252 2022-07-21T02:06:27Z Evolution and evolvability 922352 /* Banner links must be accessible on smartphones */ Reply wikitext text/x-wiki [[Category:WikiJournal]] {{WikiJournal_discussions}} {{Archive box| [[/Archive 2014–2016|2014–2016]] <br>[[/Archive 2016 naming vote|2016 naming vote]] <br>[[/Archive 2017|2017]] <br>[[/Archive 2018|2018]] <br>[[/Archive 2019|2019]] <br>[[/Archive 2020|2020]] <br>[[/Archive 2021|2021]] <br>[[/Archive 2022|2022]] Discussions may also take place at the <br>'''[https://lists.wikimedia.org/pipermail/wikijournal-en/ public mailing list]'' ([https://lists.wikimedia.org/mailman/listinfo/wikijournal-en Join]) }} {{TOClimit|limit=3}} == Banner links must be accessible on smartphones == On smartphones, the banners are hard to tap/click on, especially the Preprint one. I have difficulty changing the banners' format. [[User:George Ho|George Ho]] ([[User talk:George Ho|discuss]] • [[Special:Contributions/George Ho|contribs]]) 12:31, 29 January 2022 (UTC) :@[[User:George Ho|George Ho]]: Sorry for mising this earlier! Do you know if you were using the 'mobile view' or 'desktop view' on your smartphone? I've tried to make the tabs re-flow into a grid when on a mobie device, bit I think it only works in 'mobile view'. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:06, 21 July 2022 (UTC) == Reference deposits == Hi all! I was taking a look at the [https://www.crossref.org/members/prep/6026 WikiJournal User Group participation report] over on Crossref's site. This is a useful tool for exploring how rich the metadata that WJUG submits to Crossref along with its DOIs is. It looks like there's lots of room for improvement, some of which would be fairly straightforward to accomplish: the License URLs category, for instance, measures how many articles' metadata include a link to the license under which the papers are distributed (either CC-BY 4.0 or CC-BY-SA 4.0 typically, right?). What I wanted to look at right now was the References category, in which WJUG is currently scoring 0%. What this means is that none of the 87 articles registered for DOIs by WJUG with Crossref include the references as part of their metadata. This matters for a few reasons. First, reference linking (i.e., including DOIs in references) is required by Crossref's terms of service, and reference depositing (i.e., submitting metadata with references) is strongly encouraged. Second, the inclusion of references in metadata is how Crossref tracks citations. When you see a journal article's "What Cites This" page, you'll often see a few numbers, frequently a Crossref citation count, a Web of Science citation count, and a Google Scholar citation count. On these pages, you are often able to view which articles are specifically citing the article in question too, and in some cases, publishers may preemptively set up modules that autodisplay the citing articles alongside the article itself. This brings up the third reason to begin depositing references: not only is it good practice for good metadata management's sake itself, but it also has the capability to improve visibility for WikiJournal articles. Consider the ''WJS'' article "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]"; its first reference is the 1907 article "Parrakeets Moulting". If you visit the Taylor & Francis [https://doi.org/10.1071/MU906192f page for "Parrakeets Moulting"], however, you can see in the righthand "Related research" module in the "Cited by" tab that no articles cite this paper. Because references for WJUG articles haven't yet been deposited with Crossref, there's no way to link "Beak and feather disease virus" and "Parrakeets Moulting"; if references ''were'' deposited for this paper, then the ''WJS'' article would eventually appear as a citing article on the "Parrakeets Moulting" page. Thus, reference linking offers readers of the cited article another connection to the citing WikiJournal article, increasing the visibility of WJUG outputs. One final reason to consider depositing references is that doing so will grant WJUG eligibility for Crossref's [https://www.crossref.org/documentation/cited-by/ Cited-by service], which is essentially the tool that allows WJUG the ability to see what research is citing WikiJournal articles. Right now, WJUG can access the ''number'' of citations for each of its journals' articles through Crossref (''[http://data.crossref.org/depositorreport?pubid=J243966 WJM]'', ''[http://data.crossref.org/depositorreport?pubid=J310521 WJS]'', and ''[http://data.crossref.org/depositorreport?pubid=J310522 WJH]'') but can't actually see what those citing articles are. Depositing references will grant eligibility for Cited-by which WJUG can opt to enroll in (free!) and access said lists of citing materials for WikiJournal articles. If depositing references is of interest, the good news is that Crossref has made it pretty easy! References can be deposited manually via the [https://apps.crossref.org/SimpleTextQuery Simple Text Query] tool on Crossref's site. All one needs to do is copy the list of references from a WikiJournal article and paste it into the tool. (Note that for some articles, this will be easy; "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]" has a unified reference list, but other articles like "[[WikiJournal of Humanities/Themes in Maya Angelou's autobiographies|Themes in Maya Angelou's autobiographies]]" have references split between a footnotes and a cited by list and may need to be manually trimmed to remove the repeated "[Author], [date], p. XX" footnotes when submitting.) Simple Text Query then parses the list and connects materials based on their DOIs. Once this is done, the depositor clicks ''Deposit'', enters their email, the Parent DOI (i.e., the DOI of the article for which references are being deposited), and their Crossref depositor credentials. I have been manually going through all articles in all three journals to make sure that all of them have relevant DOIs included in their references. I have completed ''WJS'', am almost done with ''WJH'', and will then start on ''WJM''. Once this is done, I would be happy to either guide someone interested through beginning to deposit references or take over the project myself, at least to work through the 87-article backlog of existing papers. (If someone with depositor access wants to try making a reference deposit, "Beak and feather disease virus" is in good shape and its reflist is ready to be deposited.) In either case, please let me know if this is something WJUG would be interested in pursuing and how I can help. Please let me know if you have any questions. Kindly —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 01:02, 19 June 2022 (UTC) : Okay, all ''WJH'' articles now include all available DOIs. ''WJS'' is left to do. —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 20:23, 19 June 2022 (UTC) ::Thanks Colin for the very informative post and your great work on adding DOIs. I will bring this up at our next monthly meeting. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:31, 20 June 2022 (UTC) :::Great points raised! I've added a step-wise summary process [[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|here]] and we're looking at organising going through and uploading the back-catalogue. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:50, 21 July 2022 (UTC) e3wyvi54zcte1w0b3qad3ow0z5cb32r 2408290 2408255 2022-07-21T05:18:20Z Bobamnertiopsis 24451 /* Reference deposits */ re wikitext text/x-wiki [[Category:WikiJournal]] {{WikiJournal_discussions}} {{Archive box| [[/Archive 2014–2016|2014–2016]] <br>[[/Archive 2016 naming vote|2016 naming vote]] <br>[[/Archive 2017|2017]] <br>[[/Archive 2018|2018]] <br>[[/Archive 2019|2019]] <br>[[/Archive 2020|2020]] <br>[[/Archive 2021|2021]] <br>[[/Archive 2022|2022]] Discussions may also take place at the <br>'''[https://lists.wikimedia.org/pipermail/wikijournal-en/ public mailing list]'' ([https://lists.wikimedia.org/mailman/listinfo/wikijournal-en Join]) }} {{TOClimit|limit=3}} == Banner links must be accessible on smartphones == On smartphones, the banners are hard to tap/click on, especially the Preprint one. I have difficulty changing the banners' format. [[User:George Ho|George Ho]] ([[User talk:George Ho|discuss]] • [[Special:Contributions/George Ho|contribs]]) 12:31, 29 January 2022 (UTC) :@[[User:George Ho|George Ho]]: Sorry for mising this earlier! Do you know if you were using the 'mobile view' or 'desktop view' on your smartphone? I've tried to make the tabs re-flow into a grid when on a mobie device, bit I think it only works in 'mobile view'. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:06, 21 July 2022 (UTC) == Reference deposits == Hi all! I was taking a look at the [https://www.crossref.org/members/prep/6026 WikiJournal User Group participation report] over on Crossref's site. This is a useful tool for exploring how rich the metadata that WJUG submits to Crossref along with its DOIs is. It looks like there's lots of room for improvement, some of which would be fairly straightforward to accomplish: the License URLs category, for instance, measures how many articles' metadata include a link to the license under which the papers are distributed (either CC-BY 4.0 or CC-BY-SA 4.0 typically, right?). What I wanted to look at right now was the References category, in which WJUG is currently scoring 0%. What this means is that none of the 87 articles registered for DOIs by WJUG with Crossref include the references as part of their metadata. This matters for a few reasons. First, reference linking (i.e., including DOIs in references) is required by Crossref's terms of service, and reference depositing (i.e., submitting metadata with references) is strongly encouraged. Second, the inclusion of references in metadata is how Crossref tracks citations. When you see a journal article's "What Cites This" page, you'll often see a few numbers, frequently a Crossref citation count, a Web of Science citation count, and a Google Scholar citation count. On these pages, you are often able to view which articles are specifically citing the article in question too, and in some cases, publishers may preemptively set up modules that autodisplay the citing articles alongside the article itself. This brings up the third reason to begin depositing references: not only is it good practice for good metadata management's sake itself, but it also has the capability to improve visibility for WikiJournal articles. Consider the ''WJS'' article "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]"; its first reference is the 1907 article "Parrakeets Moulting". If you visit the Taylor & Francis [https://doi.org/10.1071/MU906192f page for "Parrakeets Moulting"], however, you can see in the righthand "Related research" module in the "Cited by" tab that no articles cite this paper. Because references for WJUG articles haven't yet been deposited with Crossref, there's no way to link "Beak and feather disease virus" and "Parrakeets Moulting"; if references ''were'' deposited for this paper, then the ''WJS'' article would eventually appear as a citing article on the "Parrakeets Moulting" page. Thus, reference linking offers readers of the cited article another connection to the citing WikiJournal article, increasing the visibility of WJUG outputs. One final reason to consider depositing references is that doing so will grant WJUG eligibility for Crossref's [https://www.crossref.org/documentation/cited-by/ Cited-by service], which is essentially the tool that allows WJUG the ability to see what research is citing WikiJournal articles. Right now, WJUG can access the ''number'' of citations for each of its journals' articles through Crossref (''[http://data.crossref.org/depositorreport?pubid=J243966 WJM]'', ''[http://data.crossref.org/depositorreport?pubid=J310521 WJS]'', and ''[http://data.crossref.org/depositorreport?pubid=J310522 WJH]'') but can't actually see what those citing articles are. Depositing references will grant eligibility for Cited-by which WJUG can opt to enroll in (free!) and access said lists of citing materials for WikiJournal articles. If depositing references is of interest, the good news is that Crossref has made it pretty easy! References can be deposited manually via the [https://apps.crossref.org/SimpleTextQuery Simple Text Query] tool on Crossref's site. All one needs to do is copy the list of references from a WikiJournal article and paste it into the tool. (Note that for some articles, this will be easy; "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]" has a unified reference list, but other articles like "[[WikiJournal of Humanities/Themes in Maya Angelou's autobiographies|Themes in Maya Angelou's autobiographies]]" have references split between a footnotes and a cited by list and may need to be manually trimmed to remove the repeated "[Author], [date], p. XX" footnotes when submitting.) Simple Text Query then parses the list and connects materials based on their DOIs. Once this is done, the depositor clicks ''Deposit'', enters their email, the Parent DOI (i.e., the DOI of the article for which references are being deposited), and their Crossref depositor credentials. I have been manually going through all articles in all three journals to make sure that all of them have relevant DOIs included in their references. I have completed ''WJS'', am almost done with ''WJH'', and will then start on ''WJM''. Once this is done, I would be happy to either guide someone interested through beginning to deposit references or take over the project myself, at least to work through the 87-article backlog of existing papers. (If someone with depositor access wants to try making a reference deposit, "Beak and feather disease virus" is in good shape and its reflist is ready to be deposited.) In either case, please let me know if this is something WJUG would be interested in pursuing and how I can help. Please let me know if you have any questions. Kindly —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 01:02, 19 June 2022 (UTC) : Okay, all ''WJH'' articles now include all available DOIs. ''WJM'' is left to do. —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 20:23, 19 June 2022 (UTC) ::Thanks Colin for the very informative post and your great work on adding DOIs. I will bring this up at our next monthly meeting. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:31, 20 June 2022 (UTC) :::Great points raised! I've added a step-wise summary process [[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|here]] and we're looking at organising going through and uploading the back-catalogue. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:50, 21 July 2022 (UTC) ::::Thanks {{u|Evolution and evolvability}}! I'm glad to hear it's of interest. I'm still working through adding DOIs to all references in ''WJM'' but I'll try to finish that by the end of the month so all articles in all three journals are ready to be deposited. Let me know if you have any other questions! —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 05:18, 21 July 2022 (UTC) jwbfy6f4npvordpnnndynq3lchlex18 2408336 2408290 2022-07-21T06:27:15Z George Ho 839352 /* Banner links must be accessible on smartphones */re to [[User:Evolution and evolvability]] wikitext text/x-wiki [[Category:WikiJournal]] {{WikiJournal_discussions}} {{Archive box| [[/Archive 2014–2016|2014–2016]] <br>[[/Archive 2016 naming vote|2016 naming vote]] <br>[[/Archive 2017|2017]] <br>[[/Archive 2018|2018]] <br>[[/Archive 2019|2019]] <br>[[/Archive 2020|2020]] <br>[[/Archive 2021|2021]] <br>[[/Archive 2022|2022]] Discussions may also take place at the <br>'''[https://lists.wikimedia.org/pipermail/wikijournal-en/ public mailing list]'' ([https://lists.wikimedia.org/mailman/listinfo/wikijournal-en Join]) }} {{TOClimit|limit=3}} == Banner links must be accessible on smartphones == On smartphones, the banners are hard to tap/click on, especially the Preprint one. I have difficulty changing the banners' format. [[User:George Ho|George Ho]] ([[User talk:George Ho|discuss]] • [[Special:Contributions/George Ho|contribs]]) 12:31, 29 January 2022 (UTC) :@[[User:George Ho|George Ho]]: Sorry for mising this earlier! Do you know if you were using the 'mobile view' or 'desktop view' on your smartphone? I've tried to make the tabs re-flow into a grid when on a mobie device, bit I think it only works in 'mobile view'. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:06, 21 July 2022 (UTC) :: @[[User:Evolution and evolvability|Shafee]]: Using 'mobile view' on Android, the Preprint banner is hard to tap, yet I can access that journal via tapping the icon on the left of the banner. Others are still clickable, yet larger text is annoying on mobile view. --[[User:George Ho|George Ho]] ([[User talk:George Ho|discuss]] • [[Special:Contributions/George Ho|contribs]]) 06:27, 21 July 2022 (UTC) == Reference deposits == Hi all! I was taking a look at the [https://www.crossref.org/members/prep/6026 WikiJournal User Group participation report] over on Crossref's site. This is a useful tool for exploring how rich the metadata that WJUG submits to Crossref along with its DOIs is. It looks like there's lots of room for improvement, some of which would be fairly straightforward to accomplish: the License URLs category, for instance, measures how many articles' metadata include a link to the license under which the papers are distributed (either CC-BY 4.0 or CC-BY-SA 4.0 typically, right?). What I wanted to look at right now was the References category, in which WJUG is currently scoring 0%. What this means is that none of the 87 articles registered for DOIs by WJUG with Crossref include the references as part of their metadata. This matters for a few reasons. First, reference linking (i.e., including DOIs in references) is required by Crossref's terms of service, and reference depositing (i.e., submitting metadata with references) is strongly encouraged. Second, the inclusion of references in metadata is how Crossref tracks citations. When you see a journal article's "What Cites This" page, you'll often see a few numbers, frequently a Crossref citation count, a Web of Science citation count, and a Google Scholar citation count. On these pages, you are often able to view which articles are specifically citing the article in question too, and in some cases, publishers may preemptively set up modules that autodisplay the citing articles alongside the article itself. This brings up the third reason to begin depositing references: not only is it good practice for good metadata management's sake itself, but it also has the capability to improve visibility for WikiJournal articles. Consider the ''WJS'' article "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]"; its first reference is the 1907 article "Parrakeets Moulting". If you visit the Taylor & Francis [https://doi.org/10.1071/MU906192f page for "Parrakeets Moulting"], however, you can see in the righthand "Related research" module in the "Cited by" tab that no articles cite this paper. Because references for WJUG articles haven't yet been deposited with Crossref, there's no way to link "Beak and feather disease virus" and "Parrakeets Moulting"; if references ''were'' deposited for this paper, then the ''WJS'' article would eventually appear as a citing article on the "Parrakeets Moulting" page. Thus, reference linking offers readers of the cited article another connection to the citing WikiJournal article, increasing the visibility of WJUG outputs. One final reason to consider depositing references is that doing so will grant WJUG eligibility for Crossref's [https://www.crossref.org/documentation/cited-by/ Cited-by service], which is essentially the tool that allows WJUG the ability to see what research is citing WikiJournal articles. Right now, WJUG can access the ''number'' of citations for each of its journals' articles through Crossref (''[http://data.crossref.org/depositorreport?pubid=J243966 WJM]'', ''[http://data.crossref.org/depositorreport?pubid=J310521 WJS]'', and ''[http://data.crossref.org/depositorreport?pubid=J310522 WJH]'') but can't actually see what those citing articles are. Depositing references will grant eligibility for Cited-by which WJUG can opt to enroll in (free!) and access said lists of citing materials for WikiJournal articles. If depositing references is of interest, the good news is that Crossref has made it pretty easy! References can be deposited manually via the [https://apps.crossref.org/SimpleTextQuery Simple Text Query] tool on Crossref's site. All one needs to do is copy the list of references from a WikiJournal article and paste it into the tool. (Note that for some articles, this will be easy; "[[WikiJournal of Science/Beak and feather disease virus: biology and resultant disease|Beak and feather disease virus: biology and resultant disease]]" has a unified reference list, but other articles like "[[WikiJournal of Humanities/Themes in Maya Angelou's autobiographies|Themes in Maya Angelou's autobiographies]]" have references split between a footnotes and a cited by list and may need to be manually trimmed to remove the repeated "[Author], [date], p. XX" footnotes when submitting.) Simple Text Query then parses the list and connects materials based on their DOIs. Once this is done, the depositor clicks ''Deposit'', enters their email, the Parent DOI (i.e., the DOI of the article for which references are being deposited), and their Crossref depositor credentials. I have been manually going through all articles in all three journals to make sure that all of them have relevant DOIs included in their references. I have completed ''WJS'', am almost done with ''WJH'', and will then start on ''WJM''. Once this is done, I would be happy to either guide someone interested through beginning to deposit references or take over the project myself, at least to work through the 87-article backlog of existing papers. (If someone with depositor access wants to try making a reference deposit, "Beak and feather disease virus" is in good shape and its reflist is ready to be deposited.) In either case, please let me know if this is something WJUG would be interested in pursuing and how I can help. Please let me know if you have any questions. Kindly —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 01:02, 19 June 2022 (UTC) : Okay, all ''WJH'' articles now include all available DOIs. ''WJM'' is left to do. —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 20:23, 19 June 2022 (UTC) ::Thanks Colin for the very informative post and your great work on adding DOIs. I will bring this up at our next monthly meeting. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:31, 20 June 2022 (UTC) :::Great points raised! I've added a step-wise summary process [[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|here]] and we're looking at organising going through and uploading the back-catalogue. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:50, 21 July 2022 (UTC) ::::Thanks {{u|Evolution and evolvability}}! I'm glad to hear it's of interest. I'm still working through adding DOIs to all references in ''WJM'' but I'll try to finish that by the end of the month so all articles in all three journals are ready to be deposited. Let me know if you have any other questions! —[[User:Bobamnertiopsis|Collin]] (Bobamnertiopsis)^{[[User talk:Bobamnertiopsis|t]] [[Special:Contributions/Bobamnertiopsis|c]]} 05:18, 21 July 2022 (UTC) fzv8yd1hhind6wb5qhk0dddapg7unnz 0 169944 2408395 2408155 2022-07-21T11:23:04Z ThaniosAkro 2805358 /* Z and Z^2 on polar diagram */ wikitext text/x-wiki =Objective= {{RoundBoxTop|theme=3}} [[file:Books-aj.svg_aj_ashton_01f.png|right|100px]] * Learn about Python integers. * Learn about non-decimal integers. * Learn about Python floats. * Learn about precision of floats. * Learn about Boolean algebra. (Booleans are a subclass of integers.<ref>http://docs.python.org/3.4/library/functions.html#bool</ref>) * Learn about [[Wikipedia:Complex number|complex numbers]] in Python. * Learn how to convert numbers into different basic data types. {{RoundBoxBottom}} =Lesson= {{RoundBoxTop|theme=2}} ==Data Types== This is the first of several lessons on the data types used by Python. Computer programs can process instructions that work with many different kinds of data, and the instructions need to be very precise. If you add a word to this sentence, 'add' means something very different from when you add 2 and 3. A computer language has to have a set of rules defining what operations can be applied to different kinds of data, and for this to work, there also has to be a set of rules defining exactly what data can be used with each operation. For example, if you want to calculate grossProfit = salesIncome - costs, a program has to know that these quantities are variables containing numbers rather than just strings of letters. They must have a numerical data type rather than string data type. If you are not clear about the meaning in computer science of variables and of data types, it may help to brush up on the lesson [[Introduction_to_Programming/Variables]]. ===Two useful Built-in Functions=== ====class type(object)==== With one argument, return the type of an object. <syntaxhighlight lang=Python> >>> type(6) <class 'int'> >>> >>> type(6.4) <class 'float'> >>> >>> type('6.4') <class 'str'> >>> >>> type(b'6.4') <class 'bytes'> >>> >>> type(['6.4']) <class 'list'> >>> </syntaxhighlight> ====isinstance(object, classinfo)==== Return true if the object argument is an instance of the classinfo argument. classinfo can be a tuple. isinstance() arg 2 must be a type or tuple of types. <syntaxhighlight lang=Python> >>> isinstance(6,int) True >>> >>> isinstance(6,str) False >>> >>> isinstance('6',str) True >>> >>> isinstance('6',(int,float,bytes)) False >>> >>> isinstance('6',(int,float,bytes,str)) True >>> >>> isinstance({},dict) True >>> >>> isinstance({3,4,5},set) True >>> >>> isinstance(b'',str) False >>> >>> isinstance(b'',bytes) True >>> </syntaxhighlight> {{RoundBoxBottom}} =Python Integers= {{RoundBoxTop|theme=2}} ==Introduction to integers== Python has several data types to represent numbers. This lesson introduces two: integers, and floating point numbers, or 'floats'. We'll discuss floats later in the lesson. An integer, commonly abbreviated to ''int'', is a whole number (positive, negative, or zero). So <code>7</code>, <code>0</code>, <code>-11</code>, <code>2</code>, and <code>5</code> are integers. <code>3.14159</code>, <code>0.0001</code>, <code>11.11111</code>, and even <code>2.0</code> are not integers, they are floats in Python. To test if this is true, we can use the <code>isinstance</code> built-in function to test if a number is or isn't an integer. <syntaxhighlight lang=python> >>> isinstance(7, int) True >>> isinstance(0, int) True >>> isinstance(-11, int) True >>> isinstance(2, int) True >>> isinstance(5, int) True >>> isinstance(3.14159, int) False >>> isinstance(0.0001, int) False >>> isinstance(11.11111, int) False >>> isinstance(2.0, int) False </syntaxhighlight> A decimal integer contains one or more digits "0" ... "9". Underscores may be used to improve readability. With one exception described in floats below, leading zeros in a non-zero decimal number are not allowed. We can perform simple mathematical operations with integers, like addition (<code>+</code>), subtraction (<code>-</code>), multiplication (<code>*</code>), and division (<code>/</code>). Here are some examples using simple math. <syntaxhighlight lang=Python> >>> 2+2 4 >>> 4-2 2 >>> 6+1 7 >>> 6+7-3 10 >>> 2*2 4 >>> 2*2*2 8 >>> -2 -2 >>> 8/2 4.0 >>> 4*4/2 8.0 >>> 4-4*2 -4 >>> 2-4 -2 >>> 10+10/2 15.0 </syntaxhighlight> You should have noticed three things in the above example. First, all mathematical operations follow an [[Wikipedia:Order of operations|order of operations]], called precedence; multiplication and division are done first, then addition and subtraction are performed, hence why <code>10+10/2</code> didn't result in <code>10.0</code>. Secondly, when you divide, a float is always the result. Lastly, by putting a minus sign (<code>-</code>) in front of a number, it will become a negative number. You can do more mathematical operations than the previously demonstrated ones. We can perform a ''floor division'' by using two forward slashes (<code>//</code>) to divide and have the result as an integer. <syntaxhighlight lang=python> >>> 4 // 2 2 >>> 1 // 8 0 >>> 5 // 5 1 >>> 100 // 5 20 >>> 4 // 3 1 </syntaxhighlight> Now, that may save us trouble, but what if we want to get '''just''' the [[Wikipedia:Remainder|''remainder'']] of a division? We can perform a [[Wikipedia:Modulo operation|modulo operation]] to get the remainder. To perform a modulo, use a percent sign (<code>%</code>). <syntaxhighlight lang=python> >>> 5 % 4 1 >>> 1 % 4 1 >>> 4 % 4 0 >>> 2 % 4 2 >>> 2 % 1 0 >>> 20 % 2 0 >>> 20 % 3 2 >>> -20 % 3 1 </syntaxhighlight> The <code>divmod()</code> built-in function returns both quotient and remainder: <syntaxhighlight lang=python> >>> divmod(7,3) (2, 1) >>> (q,r) = divmod(7,3) >>> q; r 2 1 </syntaxhighlight> You can also find the power of a number by using two asterisk symbols (<code>**</code>). <syntaxhighlight lang=python> >>> 4 ** 2 16 >>> 4 ** 4 256 >>> 1 ** 11278923689 1 >>> 2 ** 4 16 >>> 10 ** 2 100 >>> 1024 ** 2 1048576 >>> 10 ** 6 1000000 >>> 25 ** (-1/2) 0.2 >>> 4 * - 3 ** 2 -36 >>> 4 * (- 3) ** 2 36 >>> 8 / 4 ** 2 0.5 </syntaxhighlight> The operator of exponentiation <code>(**)</code> has higher precedence than <code>*</code> or <code>/</code> or unary <code>-.</code> If unsure of precedence, you can always use parentheses to force the desired result: <syntaxhighlight lang=python> >>> (4 * (- 3)) ** 2 ; 4 * ((- 3) ** 2) 144 36 >>> </syntaxhighlight> There is no limit for the length of integer literals apart from what can be stored in available memory. ==Non-decimal Integers== Almost everyone is familiar with ten based numbers. While base 10 is useful for everyday tasks, it isn't ideal for use in the computer world. Three other numeral systems are commonly used in computer science; binary, octal, and hexadecimal. We'll lightly cover Python's use of these in this section. The binary system is essential as all information is represented in binary form in computer hardware. Octal and hexadecimal are convenient for condensing binary numbers to a form that is more easily read by humans, while (unlike decimal) being simple to translate to or from binary. If you have difficulty with this part of the lesson, it may help to brush up on the lesson [[Numeral_systems]] in the course [[Introduction_to_Computers]]. Most people have heard of binary and it is often associated with computers. Actually, modern binary made its way into the world far before electricity was widely in use. The binary system is 2 based, which means that only two numbers are used. Of course, these numbers are 0 and 1. So <math>1+1=10_2,</math> unlike the decimal's <math>1+1=2_{10}.</math> To use binary numbers in python, prepend <code>0B</code> or <code>0b</code> to the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> <syntaxhighlight lang=python> >>> 0B11 3 >>> 0B1 + 0B1 2 >>> 0B11 + 0B1 4 >>> 0B10001 + 0B1 18 >>> 0B10001 - 0B1 16 >>> bin(2345) '0b100100101001' >>> 0b_111_0101_0011 1875 </syntaxhighlight> The value returned by <code>bin()</code> is a string. The underscore <code>(_)</code> may be used to make numbers more readable. {{Note|'''Note:''' In computers, a binary digit of information is called a [[Wikipedia:Bit|bit]].}} The octal numeral system is something that really isn't used anymore, since it was superseded by hexadecimal. The octal system made sense decades ago when hardware was expensive, because the 8 based system can fit into three [[Wikipedia:Bit|bits]] perfectly. Though this scheme fits into bits, it does not fit into a [[Wikipedia:Byte|standard byte]], which is 8 ''bits''. Since the octal numeral system is 8 based, you can only use numbers "0"..."7". To use octal numbers in python, prepend <code>0o</code> or <code>0O</code> to the beginning of the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> You may find it easier to use a lowercase o instead of an uppercase O, since it could be confused as a zero. <syntaxhighlight lang=python> >>> 0o3 3 >>> 0o12 10 >>> 0o12 + 0o10 18 >>> 0o12 - 0o03 7 >>> 0o100 64 >>> 0o777 511 >>> 0o777 - 0o111 438 >>> oct(1_234_987) '0o4554053' >>> 0o_1234_9876 File "<stdin>", line 1 0o_1234_9876 ^ SyntaxError: invalid token >>> 0o_1234_0765 2736629 </syntaxhighlight> The hexadecimal numeral system is widely used when working with computers, because one hexadecimal digit can fit into a [[Wikipedia:Nibble|nibble]] (4 bits). Since a standard ''byte'' is 8 bits, two nibbles could perfectly fit into a byte, hence why the ''octal'' system is rather obsolete. Hexadecimal has 16 digits, which consist of "0"..."9" and "A"..."F" or "a"..."f". "Letters as numbers?", you may say. Indeed, it may be tricky working with letters as numbers, but once you get comfortable with them, it will be easy to use. To use hexadecimal numbers in python, prepend <code>0x</code> or <code>0X</code> to the beginning of the number.<ref>https://docs.python.org/3/reference/lexical_analysis.html#integer-literals</ref> I suggest using a lowercase x, since it is easier to distinguish from the numbers and uppercase letters. <syntaxhighlight lang=python> >>> 0xF 15 >>> 0xF0 240 >>> 0xFF - 0xF 240 >>> 0xF + 0xA 25 >>> 0x2 + 0x2 4 >>> 0x12 - 0xA 8 >>> 0xFF / 0xF 17.0 >>> 0xF * 0xF 225 >>> hex(1_234_987) '0x12d82b' >>> 0x_12_D82B 1234987 </syntaxhighlight> {{Note|'''Note:''' You '''do not''' have to use just uppercase letters when working with hexadecimal, you can also use lowercase letters if you find it easier.}} This topic has been lightly brushed up on and will probably not be used until later in advanced lessons. If you feel a need to learn this, or you want to be proficient at it, the course [[Introduction to Computers]] has a lesson called [[Numeral systems]] that deals with these numeral systems with a little more in depth teaching. ===Bitwise Operators=== All integers may be tested or modified by the [https://docs.python.org/3/library/stdtypes.html#bitwise-operations-on-integer-types Bitwise Operators]: <code>&</code> (and), <code>|</code> (or), <code>^</code> (exclusive or), <code><<</code> (shift left), <code>>></code> (shift right) and <code>~</code> (invert). However it makes good sense to confine our description of these operators to non-decimal integers, particularly binary and hexadecimal. These operators are called 'bitwise' because they operate on individual bits within the integer. 1. The <code>&</code> operator produces a true output when both corresponding bits are true: <syntaxhighlight lang=python> >>> bin (0b1010101 & 0b1111) '0b101' >>> bin (0b1010101 & 0b111000) '0b10000' >>> hex (0xFF00FF & 0xFF00) '0x0' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1111 ^ ^ </syntaxhighlight> have the marked bits set and the result is <code>'0b101'.</code> 2. The <code>|</code> operator produces a true output when at least one of both corresponding bits is true: <syntaxhighlight lang=python> >>> bin (0b1010101 | 0b1110) '0b1011111' >>> bin (0b1010101 | 0b1100) '0b1011101' >>> hex (0xFF00FF | 0x3F0) '0xff03ff' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1110 ^ ^^^^^ </syntaxhighlight> have the marked bits set in at least one of the operands and the result is <code>'0b1011111'.</code> 3. The <code>^</code> operator produces a true output when exactly one of both corresponding bits is true: <syntaxhighlight lang=python >>> bin (0b1010101 ^ 0b1110) '0b1011011' >>> bin (0b1010101 ^ 0b1100) '0b1011001' >>> hex (0xFF00FF ^ 0x3F0) '0xff030f' </syntaxhighlight> In the first example both input operands <syntaxhighlight lang=python> 0b1010101 0b 1110 ^ ^^ ^^ </syntaxhighlight> have the marked bits set in exactly one of the operands and the result is <code>'0b1011011'.</code> 4. The <code> << </code> operator shifts the operand left by the number of bits specified: <syntaxhighlight lang=python >>> bin(0b10101 << 2) '0b1010100' >>> bin(0b10101 << 5) '0b1010100000' >>> hex(0xFF00FF << 8) '0xff00ff00' >>> (0xFF00FF << 8) == (0xFF00FF * 2**8) True </syntaxhighlight> In the first example the output is the input shifted left 2 bits: <syntaxhighlight lang=python> 0b 10101 0b1010100 ^^ </syntaxhighlight> The ouput is the input with two 0's at the right hand end. 5. The <code> >> </code> operator shifts the operand right by the number of bits specified: <syntaxhighlight lang=python >>> bin(0b10101 >> 2) '0b101' >>> bin(0b10101 >> 5) '0b0' >>> hex(0xFF00FF >> 8) '0xff00' >>> (0xFF00FF >> 8) == (0xFF00FF // 2**8) True </syntaxhighlight> In the first example the output is the input shifted right 2 bits: <syntaxhighlight lang=python> 0b10101 0b 101 </syntaxhighlight> The rightmost two bits of the input are lost forever. If you wish to preserve the 2 rightmost bits of the input, before shifting execute: <syntaxhighlight lang=python> twoBits = operand & 0x3 </syntaxhighlight> The bitwise operators above perform as expected on all integers of (almost) unlimited length: <syntaxhighlight lang=python> >>> hex( ( 0x1234_FEDC << 120 ) | ( 0x_CDE_90AB << 60 ) ) '0x1234fedc00000000cde90ab000000000000000' >>> hex( ( 0x1234_FEDC << 200 ) ^ ( 0x_CDE_90AB << 207 ) ) '0x67d7cab5c00000000000000000000000000000000000000000000000000' </syntaxhighlight> 6. The behavior of the invert (~) operator shows that negative numbers are treated as their 2’s complement value: <syntaxhighlight lang=Python> >>> a = 0b1100101100101 ; bin(~a) '-0b1100101100110' </syntaxhighlight> For a true 1's complement bitwise invert here is one way to do it: <syntaxhighlight lang=Python> >>> a = 0b1100101100101 ; b = a ^ ( (1 << a.bit_length()) - 1 ); bin(b) '0b11010011010' >>> c = a + b; bin(c) '0b1111111111111' # to test the operation, all bits of c should be set. >>> (c+1) == ( 1 << (c.bit_length()) ) True # they are. </syntaxhighlight> And another way to do it: <syntaxhighlight lang=python> from decimal import * a = 0b11100100011001110001010111 # a is int b = bin(a) # b is string print ('a =', b) formerPrecision = getcontext().prec getcontext().prec = a.bit_length() d = Decimal.logical_invert( Decimal( b[2:] ) ) # d is Decimal object. getcontext().prec = formerPrecision print ('d =', d) e = int(str(d),2) # e is int print ('e =', bin(e)) ( (a + e) == ( ( 1 << a.bit_length() ) - 1 ) ) and print ('successful inversion') </syntaxhighlight> When you execute the above code, you see the following results: <syntaxhighlight lang=python> a = 0b11100100011001110001010111 d = 11011100110001110101000 e = 0b11011100110001110101000 successful inversion </syntaxhighlight> The Decimal.logical_invert() performs a 1's complement inversion. {{RoundBoxBottom}} =Python Floats= ==Introduction to floats== {{RoundBoxTop|theme=5}} Although integers are great for many situations, they have a serious limitation, integers are [[Wikipedia:Natural number|whole numbers]]. This means that they do not include all [[Wikipedia:Real number|real numbers]]. A ''real number'' is a value that represents a quantity along a continuous line<ref>[[Wikipedia:Real number]]</ref>, which means that it can have fractions in decimal forms. <code>4.5</code>, <code>1.25</code>, and <code>0.75</code> are all real numbers. In computer science, real numbers are represented as floats. To test if a number is float, we can use the <code>isinstance</code> built-in function. <syntaxhighlight lang=python> >>> isinstance(4.5, float) True >>> isinstance(1.25, float) True >>> isinstance(0.75, float) True >>> isinstance(3.14159, float) True >>> isinstance(2.71828, float) True >>> isinstance(1.0, float) True >>> isinstance(271828, float) False >>> isinstance(0, float) False >>> isinstance(0.0, float) True </syntaxhighlight> As a general rule of thumb, floats have a ''[[Wikipedia:Decimal mark|decimal point]]'' and integers do not have a ''decimal point''. So even though <code>4</code> and <code>4.0</code> are the same number, <code>4</code> is an integer while <code>4.0</code> is a float. The basic arithmetic operations used for integers will also work for floats. (Bitwise operators will not work with floats.) <syntaxhighlight lang=python> >>> 4.0 + 2.0 6.0 >>> -1.0 + 4.5 3.5 >>> 1.75 - 1.5 0.25 >>> 4.13 - 1.1 3.03 >>> 4.5 // 1.0 4.0 >>> 4.5 / 1.0 4.5 >>> 4.5 % 1.0 0.5 >>> 7.75 * 0.25 1.9375 >>> 0.5 * 0.5 0.25 >>> 1.5 ** 2.0 2.25 </syntaxhighlight> {{RoundBoxBottom}} ==Some technical information about 'floats.'== A floating point literal can be either pointfloat or exponentfloat. A pointfloat contains a decimal point <code>(".")</code> and at least one digit <code>("0"..."9"),</code> for example: <code>34.45 ; 34. ; .45 ; 0. ; -.00 ; -33. ;</code> An exponentfloat contains an exponent which <code>::= ("e" | "E")["+" | "-"]decinteger.</code> <code>("e" | "E")</code> means that <code>"e"</code> or <code>"E"</code> is required. <code>["+" | "-"]</code> means that <code>"+"</code> or <code>"-"</code> is optional. <code>decinteger</code> means decimal integer. <code></code><code></code> These are examples of exponents: <code>e9 ; e-0 ; e+1 ; E2 ; E-3 ; E+4 ;</code> The exponent is interpreted as follows: <math>.5e2 = .5(10^2) = 50.0;</math> <math>-3E1 = -3.0(10^1) = -30.0;</math> <math>.003e-5 = .003(10^{-5}) = 3e-08;</math> <math>3e0 = 3.0(10^{0}) = 3.0;</math> <math>0090.5e-02 = 90.5(10^{-2}) = 0.905;</math> <math>0E0 = 0.0(10^0) = 0.0;</math> An exponent float can be either: decinteger exponent, for example: <code>0e0 ; -3e1 ; 15E-6 ;</code> or pointfloat exponent, for example: <code>.5E+2 ; -3.00e-5 ; 123_456.75E-5 ;</code> The separate parts of a floating point number are: <code>1.2345 = 12345e-4 = </code> <math>\underbrace{12345}_\text{significand} \times \underbrace{10}_\text{base}\!\!\!\!\!\!^{\overbrace{-4}^\text{exponent}}.</math> <ref>https://en.wikipedia.org/wiki/Floating-point_arithmetic#Floating-point_numbers</ref> The <code>significand</code> may be called <code>mantissa</code> or <code>coefficient.</code> The <code>base</code> may be called <code>radix.</code> The <code>exponent</code> may be called <code>characteristic</code> or <code>scale.</code> Within the floating point literal white space is not permitted. An underscore <code>("_")</code> may be used to improve readability. Integer and exponent parts are always interpreted using radix <code>10.</code> Within the context of floating point literals, a "decinteger" may begin with a <code>"0".</code> Numeric literals do not include a sign; a phrase like <code>-1</code> is actually an expression composed of the unary operator <code>-</code> and the literal <code>1.</code> ===sys.float_info=== Object <code>sys.float_info</code> contains information about floats: <syntaxhighlight lang=python> >>> import sys >>> print ( '\n'.join(str(sys.float_info).split(', ')) ) sys.float_info(max=1.7976931348623157e+308 # maximum representable finite float max_exp=1024 max_10_exp=308 min=2.2250738585072014e-308 # minimum positive normalized float min_exp=-1021 min_10_exp=-307 dig=15 # maximum number of decimal digits that can be faithfully represented in a float mant_dig=53 # float precision: the number of base-radix digits in the significand of a float epsilon=2.220446049250313e-16 radix=2 # radix of exponent representation rounds=1) >>> </syntaxhighlight> Information about some of the above values follows: ====sys.float_info.mant_dig==== <syntaxhighlight lang=python> >>> sys.float_info.mant_dig 53 >>> >>> sys.float_info[7] 53 >>> >>> I1 = (1<<53) - 1 ; I1 ; hex(I1) ; I1.bit_length() 9007199254740991 '0x1fffffffffffff' 53 >>> float(I1-1) ; float(I1-1) == I1-1 9007199254740990.0 True >>> float(I1) ; float(I1) == I1 9007199254740991.0 True >>> float(I1+1) ; float(I1+1) == I1+1 9007199254740992.0 True >>> float(I1+2) ; float(I1+2) == I1+2 9007199254740992.0 # Loss of precision occurs here. False >>> >>> I2 = I1 - 10**11 ; I2 ; hex(I2) ; I2.bit_length() ; float(I2) == I2 ; len(str(I2)) 9007099254740991 '0x1fffe8b78917ff' 53 True # I2 can be accurately represented as a float. 16 >>> I3 = I1 + 10**11 ; I3 ; hex(I3) ; I3.bit_length() ; float(I3) == I3 ; len(str(I3)) 9007299254740991 '0x2000174876e7ff' 54 # Too many bits. False # I3 can not be accurately represented as a float. 16 >>> </syntaxhighlight> ====sys.float_info.dig==== <syntaxhighlight lang=python> >>> len(str(I1)) 16 >>> >>> sys.float_info.dig 15 >>> sys.float_info[6] 15 >>> </syntaxhighlight> As shown above some (but not all) decimal numbers of 16 digits can be accurately represented as a float. Hence 15 as the limit in <code>sys.float_info.dig</code>. ====sys.float_info.max==== <syntaxhighlight lang=python> >>> sys.float_info.max 1.7976931348623157e+308 >>> >>> sys.float_info[0] 1.7976931348623157e+308 >>> >>> 1.7976931348623157e+305 1.7976931348623156e+305 >>> 1.7976931348623157e+306 1.7976931348623156e+306 >>> 1.7976931348623157e+307 1.7976931348623158e+307 >>> 1.7976931348623157e+308 1.7976931348623157e+308 >>> 1.7976931348623157e+309 inf >>> </syntaxhighlight> ====sys.float_info.min==== <syntaxhighlight lang=python> >>> sys.float_info.min 2.2250738585072014e-308 >>> sys.float_info[3] 2.2250738585072014e-308 >>> >>> 2.2250738585072014e-306 2.2250738585072014e-306 >>> 2.2250738585072014e-307 2.2250738585072014e-307 >>> 2.2250738585072014e-308 2.2250738585072014e-308 >>> 2.2250738585072014e-309 2.225073858507203e-309 # Loss of precision. >>> 2.2250738585072014e-310 2.2250738585072e-310 >>> 2.2250738585072014e-311 2.225073858507e-311 >>> </syntaxhighlight> ==The Precision of Floats== Before you start calculating with floats you should understand that the precision of floats has limits, due to Python and the architecture of a computer. Some examples of errors due to finite precision are displayed below. <syntaxhighlight lang=Python> >>> 1.13 - 1.1 0.029999999999999805 >>> 0.001 / 11.11 9.000900090009002e-05 >>> 1 + .0000000000000001 1.0 >>> -5.5 % 3.2 0.9000000000000004 >>> float(1_234_567_890_123_456) 1234567890123456.0 >>> float(12_345_678_901_234_567) 1.2345678901234568e+16 </syntaxhighlight> In the first example, <code>1.13 - 1.1 = 0.03</code>, although Python comes to the conclusion that the real answer is <code>0.029999999999999805</code>. The fact behind this reasoning is based on how the computer stores memory, so the ''[[Wikipedia:Subtraction|difference]]'' lost a little of its precision. As the ''minuend'' increases in size, so does its precision. <code> 2.13 - 1.1 = 1.0299999999999998 </code> and <code>3.13 - 1.1 = 2.03</code>. In the second example, <code>0.001 / 11.11 = 9.000900090009002e-05</code> where <code>e-05</code> means ten to the power of negative five. The answer could also be <code>9.000900090009001e-05</code> depending on how the ''[[Wikipedia:Quotient|quotient]]'' is rounded, how long the quotient can be stored on the computer, and the most significant number on the right hand side. In the third example, the ''[[Wikipedia:Addition|sum]]'' of the ''addends'' <code>1 + .0000000000000001 = 1.0</code> although we know that it really is <code>1 + .0000000000000001 = 1.0000000000000001</code>. The reason the second addend is left out is because of its insignificance. Although this might not matter for every day situations, it may be important for such uses as rocket science and possibly calculus. The fourth example gives the correct result if rewritten: <syntaxhighlight lang=Python> >>> ((-5.5*10 ) % (3.2*10)) / 10.0 0.9 </syntaxhighlight> When working with Python floats, we need to be aware that there will probably be a margin of error. ==Decimal fixed point and floating point arithmetic for extreme precision== The Python [https://docs.python.org/3/library/decimal.html#module-decimal "Decimal"] module provides support for fast correctly-rounded decimal floating point arithmetic. The module offers several advantages over the float datatype, including: * Decimal numbers can be represented exactly. * The decimal module has a user alterable precision (defaulting to 28 places) which can be as large as needed for a given problem. The usual start to using decimals is importing the module, viewing the current context with getcontext() and, if necessary, setting new values for precision, rounding, or enabled traps: <syntaxhighlight lang=Python> >>> from decimal import * >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> setcontext(ExtendedContext) >>> getcontext() Context(prec=9, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[]) >>> setcontext(BasicContext) >>> getcontext() Context(prec=9, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) >>> c = getcontext() >>> c.flags[Inexact] = True >>> c.flags[FloatOperation] = True >>> c.flags[Rounded] = True >>> getcontext() Context(prec=9, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) >>> getcontext().prec = 75 # set desired precision >>> getcontext() Context(prec=75, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[Inexact, FloatOperation, Rounded], traps=[Clamped, InvalidOperation, DivisionByZero, Overflow, Underflow]) </syntaxhighlight> We are now ready to use the decimal module. <syntaxhighlight lang=Python> >>> Decimal(3.14) # Input to decimal() is float. Decimal('3.140000000000000124344978758017532527446746826171875') # Exact value of float 3.14. >>> Decimal('3.14') # Input to decimal() is string. Decimal('3.14') # Exact value of 3.14 in decimal floating point arithmetic. </syntaxhighlight> <math>(\sqrt{2})^2</math> <syntaxhighlight lang=Python> >>> (2 ** 0.5)**2 2.0000000000000004 # Result of binary floating point operation. We expect 2. >>> (Decimal('2') ** Decimal('0.5')) ** Decimal('2') Decimal('1.99999999999999999999999999999999999999999999999999999999999999999999999999') # Result of decimal floating point operation with string input. We expect 2. </syntaxhighlight> <math>(2.12345678^{(\frac{1}{2.345})})^{2.345}</math> <syntaxhighlight lang=Python> >>> (2.12345678 ** (1/2.345)) ** 2.345 2.1234567800000006 # Result of floating point operation. We expect 2.12345678. >>> (Decimal('2.12345678') ** (Decimal('1')/Decimal('2.345'))) ** Decimal('2.345') Decimal('2.12345677999999999999999999999999999999999999999999999999999999999999999999') # Result of decimal floating point operation with string input . We expect 2.12345678. >>> getcontext().rounding=ROUND_UP >>> (Decimal('2.12345678') ** (Decimal('1')/Decimal('2.345'))) ** Decimal('2.345') Decimal('2.12345678000000000000000000000000000000000000000000000000000000000000000003') # Result of decimal floating point operation with string input . We expect 2.12345678. </syntaxhighlight> Some mathematical functions are also available to Decimal: <syntaxhighlight lang=Python> >>> getcontext().prec = 30 >>> Decimal(2).sqrt() Decimal('1.41421356237309504880168872421') >>> (Decimal(2).sqrt())**2 Decimal('2.00000000000000000000000000001') # We expect 2. >>> Decimal(1).exp() Decimal('2.71828182845904523536028747135') # Value of 'e', base of natural logs. >>> Decimal( Decimal(1).exp() ).ln() Decimal('0.999999999999999999999999999999') # We expect 1. </syntaxhighlight> ==Lack of precision in the real world== (included for philosophical interest) <syntaxhighlight lang=Python> >>> a = 899_999_999_999_999.1 ; a - (a - .1) 0.125 >>> 1.13 - 1.1 0.029999999999999805 </syntaxhighlight> Simple tests indicate that the error inherent in floating point operations is about <math>\frac{1}{10^{16}}.</math> This raises the question "How much precision do we need?" For decades high school students calculated sines and cosines to 4 decimal places by referring to printed look-up tables. Before computers engineers used slide rules to make calculations accurate to about <math>\frac{1}{1000}</math> for most calculations, and the Brooklyn Bridge is still in regular use. With accuracy of <math>\frac{1}{10^{16}}</math> engineers can send a rocket to Pluto and miss by 1cm. If your calculations produce a result of <math>1.0(10^{-14})</math> and you were expecting <math>0,</math> will you be satisfied with your work? If your calculations were in meters, probably yes. If your calculations were in nanometers (<math>10^{-9}</math> of a meter), probably no. Knowing that lack of precision is inherent in floating point operations, you may have to include possibly substantial amounts of code to make allowances for it. ==Extreme Precision== (included for historical interest) If you must have a result correct to 50 places of decimals, Python's integer math comes to the rescue. Suppose your calculation is: <math>123456.789 / 4567.87654 </math> <math>= \frac{123456.789 }{4567.87654 } </math> <math>= \frac{123456.78900 }{4567.87654 }</math> <math>= \frac{12345678900 }{456787654 }.</math> For 50 significant digits after the decimal point your calculation becomes: <math>123456.789 / 4567.87654 </math> <math>= \frac{12345678900(10^{51}) }{456787654(10^{51}) }</math> <math>= \frac{12345678900(10^{51}) }{456787654 }/10^{51}.</math> <syntaxhighlight lang=python> >>> dividend = 12345678900 >>> divisor = 456787654 >>> >>> (quotient, remainder) = divmod(dividend*(10**51), divisor) ; quotient;remainder 27027172892899596625262555804540198890751981663672547 231665262 >>> if remainder >= ((divisor + (divisor & 1)) >> 1) : quotient += 1 ... >>> quotient 27027172892899596625262555804540198890751981663672548 >>> </syntaxhighlight> The correct result <math>= 27027172892899596625262555804540198890751981663672548(10^{-51}),</math> but note: <syntaxhighlight lang=python> >>> quotient*(10**(-51)) 27.027172892899596 # Lack of precision. >>> </syntaxhighlight> Put the decimal point in the correct position within a string to preserve precision: <syntaxhighlight lang=python> >>> str(quotient)[0:-51] + '.' + str(quotient)[-51:] '27.027172892899596625262555804540198890751981663672548' >>> </syntaxhighlight> Format the result: <syntaxhighlight lang=python> >>> s1 = str(quotient)[-51:] ; s1 '027172892899596625262555804540198890751981663672548' >>> L2 = [ s1[p:p+5] for p in range(0,51,5) ] ; L2 ['02717', '28928', '99596', '62526', '25558', '04540', '19889', '07519', '81663', '67254', '8'] >>> decimal = '_'.join(L2) ; decimal '02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8' >>> str(quotient)[0:-51] + '.' + decimal '27.02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8' # The result formatted for clarity and accurate to 50 places of decimals. >>> </syntaxhighlight> Both strings <code>'27.027172892899596625262555804540198890751981663672548'</code> and <code>'27.02717_28928_99596_62526_25558_04540_19889_07519_81663_67254_8'</code> are acceptable as input to Python's Decimal module. ==Lack of precision and what to do about it== Lack of precision in floating point operations quickly becomes apparent: <syntaxhighlight lang=python> sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : sum += increment print ('count= {}, sum = {}'.format(count,sum)) if sum != count/10_000_000_000 : break </syntaxhighlight> <pre> count= 1, sum = 1e-10 count= 2, sum = 2e-10 count= 3, sum = 3e-10 count= 4, sum = 4e-10 count= 5, sum = 5e-10 count= 6, sum = 6e-10 count= 7, sum = 7e-10 count= 8, sum = 7.999999999999999e-10 </pre> The problem seems to be that floating point numbers are contained in 53 bits, limiting the number of significant digits in the decimal number displayed to 15 or 16. But this is not really the problem. If the standard limits the number of significant digits displayed to 15 or 16, so be it. The real problem is that underlying calculations are also performed in 53 bits. <syntaxhighlight lang=python> >>> (0.000_000_000_1).hex() '0x1.b7cdfd9d7bdbbp-34' >>> h1 = '0x1b7cdfd9d7bdbbp-86' # increment with standard precision. >>> float.fromhex(h1) 1e-10 >>> </syntaxhighlight> ===Precision greater than standard=== {{RoundBoxTop|theme=2}} Rewrite the above code so that the value <code>increment</code> has precision greater than standard. <code>increment</code><math> = \frac{1}{10^{10}} = \frac{x}{16^{26}};\ x = \frac{16^{26}}{10^{10}}</math> <syntaxhighlight lang=python> >>> x,r = divmod (16**26,10**10) ;x;r 2028240960365167042394 7251286016 >>> x += (r >= (10**10)/2);x 2028240960365167042395 >>> h1 = hex(x)[2:].upper();h1 '6DF37F675EF6EADF5B' >>> increment = '0x' + h1 + 'p-104' ; increment '0x6DF37F675EF6EADF5Bp-104' # Current value of increment. >>> int(increment[:-5],16).bit_length() 71 # Greater precision than standard by 18 bits. >>> float.fromhex(increment) 1e-10 >>> </syntaxhighlight> Exact value of increment: <syntaxhighlight lang=python> >>> from decimal import * >>> Decimal(x) / Decimal(16**26) Decimal('1.0000_0000_0000_0000_0000_01355220626007433600102690740628157139990861423939350061118602752685546875E-10') >>> # 22 significant digits. </syntaxhighlight> <syntaxhighlight lang=python> sum = '0x0p0' for count in range(1,1000) : hex_val = sum.partition('p')[0] sum = hex( eval(hex_val) + x ) + 'p-104' f1 = float.fromhex(sum) print ( 'count = {}, sum = {}, sum as float = {}'.format(count, sum, f1) ) if f1 != count/10_000_000_000 : exit(99) </syntaxhighlight> <pre> count = 1, sum = 0x6df37f675ef6eadf5bp-104, sum as float = 1e-10 count = 2, sum = 0xdbe6fecebdedd5beb6p-104, sum as float = 2e-10 count = 3, sum = 0x149da7e361ce4c09e11p-104, sum as float = 3e-10 ........................... count = 997, sum = 0x1ac354f2d94d7a0b7dd67p-104, sum as float = 9.97e-08 count = 998, sum = 0x1aca342acfc3697a2bcc2p-104, sum as float = 9.98e-08 count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, sum as float = 9.99e-08 </pre> Consider the last line above: <code>count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, f1 = 9.99e-08</code>. The most accurate hex representation of value <code>9.99e-08</code> with this precision is in fact <code>'0x1ad11362c63958e8d9b0ap-104'</code> different from the above value by <code>'0x113p-104'</code>. If counting continues, drift increases but, as a fraction of sum, it remains fairly constant, apparently enabling accurate counting up to and including the theoretical limit of floats (15 decimal digits.) <pre> drift vvv count = 999, sum = 0x1ad11362c63958e8d9c1dp-104, sum as float = 9.99e-08 0x1AD11362C63958E8D9B0Ap-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 69 bits drift vvvvv count = 99999, sum = 0xa7c53e539be0252c255b85p-104, sum as float = 9.9999e-06 0xA7C53E539BE0252C24F026p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^ 17 hex digits = 68 bits drift vvvvvvvv count = 9999999999, sum = 0xffffffff920c8098a1aceb2ca5p-104, sum as float = 0.9999999999 0xFFFFFFFF920C8098A1091520A5p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 72 bits drift 15 decimal digits vvvvvvvvvvvvv count = 999999999999999, sum = 0x1869fffffffff920c81929f8524a0a5p-104, sum as float = 99999.9999999999 0x1869FFFFFFFFF920C8098A1091520A5p-104 most accurate hex representation of sum as float ^^^^^^^^^^^^^^^^^^ 18 hex digits = 69 bits </pre> {{RoundBoxTop|theme=2}} Exact value of sum: <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec=150 >>> >>> top = Decimal(0x1869fffffffff920c81929f8524a0a5); top Decimal('2028240960365165014154039634832957605') >>> bottom = Decimal(1<<104); bottom Decimal('20282409603651670423947251286016') >>> >>> d1 = top/bottom; d1 # Exact value of sum. Decimal('99999.99999999990000001355220626007432244882064733194557037300120795782210070257178813335485756397247314453125') >>> len(str(d1)) 110 >>> float(d1) 99999.9999999999 </syntaxhighlight> {{RoundBoxBottom}} While floating point operations implemented in software might not depend on conversion to and from hex strings, the above illustrates the accuracy that could be obtained if floating point software of selectable precision were to replace now antiquated floating point hardware. Python's decimal module allows floating point calculations of (almost) infinite precision, but importing a special module to perform a calculation like <math>1.13 - 1.1</math> seems onerous. <syntaxhighlight lang=python> >>> 1.13 - 1.1 0.029999999999999805 >>> </syntaxhighlight> In a programming language as magnificent as Python, the above result is intolerable. {{RoundBoxBottom}} ===Python's Decimal module=== {{RoundBoxTop|theme=2}} With a few simple changes the above counting loop takes full advantage of Python's Decimal module, and possible loss of precision becomes irrelevant. <syntaxhighlight lang=python> from decimal import * def D(v1) : return Decimal(str(v1)) sum = 0 increment = D(0.000_000_000_1) for count in range(1,1000) : sum += increment print ('count = {}, sum = {}'.format(count,sum)) if sum != count * increment : exit (99) exit (0) </syntaxhighlight> <pre> count = 1, sum = 1E-10 count = 2, sum = 2E-10 count = 3, sum = 3E-10 ................. count = 997, sum = 9.97E-8 count = 998, sum = 9.98E-8 count = 999, sum = 9.99E-8 </pre> A float is displayed with 'e', a Decimal object with 'E'. <syntaxhighlight lang=python> >>> 9.99E-8 9.99e-08 >>> Decimal(str(9.99e-8)) Decimal('9.99E-8') >>> </syntaxhighlight> {{RoundBoxBottom}} ===Reset the float=== ====Using formatted string==== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : sum += increment s1 = '{0:.10f}'.format(sum) sum = float(s1) print ('count= {}, sum = {}'.format(count,sum)) if sum != count / 10_000_000_000 : exit (99) exit (0) </syntaxhighlight> <pre> count= 1, sum = 1e-10 count= 2, sum = 2e-10 count= 3, sum = 3e-10 ................. count= 997, sum = 9.97e-08 count= 998, sum = 9.98e-08 count= 999, sum = 9.99e-08 </pre> {{RoundBoxBottom}} ====Using Decimal precision==== {{RoundBoxTop|theme=2}} Python's floating point standard states that the best accuracy to be expected is 15 significant decimal digits. <syntaxhighlight lang=python> from decimal import * getcontext().prec = 15 sum = 0 increment = 0.000_000_000_1 for count in range(1,1000) : print ( 'count =', (' '+str(count))[-3:], end=' ' ) sum += increment d1 = Decimal(str(sum)) print ( 'd1 = sum =', (' ' + str(d1))[-21:], end=' ' ) d1 += 0 # This forces d1 to conform to 15 digits of precision. print ( 'd1 =', (' ' + str(d1))[-20:], end=' ' ) sum = float(d1) print ('sum =', sum) if sum != count / 10_000_000_000 : print (' ', sum, count, increment, count*increment) exit (99) exit (0) </syntaxhighlight> <pre> count = 1 d1 = sum = 1E-10 d1 = 1E-10 sum = 1e-10 count = 2 d1 = sum = 2E-10 d1 = 2E-10 sum = 2e-10 count = 3 d1 = sum = 3E-10 d1 = 3E-10 sum = 3e-10 count = 4 d1 = sum = 4E-10 d1 = 4E-10 sum = 4e-10 count = 5 d1 = sum = 5E-10 d1 = 5E-10 sum = 5e-10 count = 6 d1 = sum = 6E-10 d1 = 6E-10 sum = 6e-10 count = 7 d1 = sum = 7E-10 d1 = 7E-10 sum = 7e-10 count = 8 d1 = sum = 7.999999999999999E-10 d1 = 8.00000000000000E-10 sum = 8e-10 count = 9 d1 = sum = 9E-10 d1 = 9E-10 sum = 9e-10 count = 10 d1 = sum = 1E-9 d1 = 1E-9 sum = 1e-09 count = 11 d1 = sum = 1.1000000000000001E-9 d1 = 1.10000000000000E-9 sum = 1.1e-09 count = 12 d1 = sum = 1.2E-9 d1 = 1.2E-9 sum = 1.2e-09 count = 13 d1 = sum = 1.3E-9 d1 = 1.3E-9 sum = 1.3e-09 count = 14 d1 = sum = 1.4000000000000001E-9 d1 = 1.40000000000000E-9 sum = 1.4e-09 count = 15 d1 = sum = 1.5E-9 d1 = 1.5E-9 sum = 1.5e-09 count = 16 d1 = sum = 1.6E-9 d1 = 1.6E-9 sum = 1.6e-09 .............................. count = 296 d1 = sum = 2.96E-8 d1 = 2.96E-8 sum = 2.96e-08 count = 297 d1 = sum = 2.97E-8 d1 = 2.97E-8 sum = 2.97e-08 count = 298 d1 = sum = 2.9800000000000002E-8 d1 = 2.98000000000000E-8 sum = 2.98e-08 count = 299 d1 = sum = 2.9899999999999996E-8 d1 = 2.99000000000000E-8 sum = 2.99e-08 count = 300 d1 = sum = 3.0000000000000004E-8 d1 = 3.00000000000000E-8 sum = 3e-08 count = 301 d1 = sum = 3.01E-8 d1 = 3.01E-8 sum = 3.01e-08 count = 302 d1 = sum = 3.02E-8 d1 = 3.02E-8 sum = 3.02e-08 .............................. count = 997 d1 = sum = 9.97E-8 d1 = 9.97E-8 sum = 9.97e-08 count = 998 d1 = sum = 9.98E-8 d1 = 9.98E-8 sum = 9.98e-08 count = 999 d1 = sum = 9.989999999999999E-8 d1 = 9.99000000000000E-8 sum = 9.99e-08 </pre> The last line: count = 999<math>\ \ \ \ </math> d1 = sum = <math>\ \ \underbrace{9.9899\_9999\_9999\_999}_\text{16 significant digits}</math>E-8<math>\ \ \ \ </math> d1 = <math>\ \ \underbrace{9.9900\_0000\_0000\_00}_\text{15 significant digits}</math>E-8<math>\ \ \ \ </math> sum = 9.99e-08 The value <code>9.9900_0000_0000_00</code> means that this is the most accurate value for <code>d1</code> that can fit in 15 significant digits. {{RoundBoxBottom}} =The Boolean= {{RoundBoxTop|theme=2}} In Python and most languages, a [[Wikipedia:Boolean data type|Boolean]] can be either <code>True</code> or <code>False</code>. A Boolean is a special data type and is a subclass of int.<ref>http://docs.python.org/3.4/library/functions.html#bool</ref> Since a Boolean has two states and only one at a time, a Boolean creates a special relationship between things. We can think of some Boolean values that we deal with in real life, for example: on or off, hot or cold, light or darkness, etc. Although a Boolean can be <code>True</code> or <code>False</code> a ''Boolean expression'' can take a statement, like <code>1 == 1</code> or <code>1 == 0</code>, and turn it into a Boolean, <code>True</code> for the former and <code>False</code> for the latter. We can use the <code>bool()</code> method to check the Boolean value of an object, which will be <code>False</code> for integer zero and for objects (numerical and other data types) that are empty, and <code>True</code> for anything else. <syntaxhighlight lang=python> >>> 1 == 1 True >>> 1 == 0 False >>> bool(0) False >>> bool(1) True >>> bool(10001219830) True >>> bool(-1908) True >>> bool("Hello!") True >>> bool("") False >>> bool(" ") True >>> bool(None) False >>> bool(0.000000000000000000000000000000000) False >>> bool("0.000000000000000000000000000000000") True >>> bool(0.0) False >>> bool([]) False >>> bool([1, 2, 3]) True >>> bool() False >>> bool(True) True >>> bool(False) False >>> bool(1==1) True >>> bool(1==0) False </syntaxhighlight> {{Note|'''Note:''' <code>True</code> and <code>False</code> are both case-sensitive, which means that you must type them exactly as shown, otherwise you'll get a syntax error.}} You can also use three operators to alter a Boolean statement<ref>https://docs.python.org/3//library/stdtypes.html#boolean-operations-and-or-not</ref>: <code>or</code>, <code>and</code>, <code>not</code>. You can use an <code>or</code> statement to allow one or more Booleans to be False so long as one is True. An <code>and</code> statement requires all of the Booleans to be True for it be True. The <code>not</code> statement reverses a Boolean so <code> not True</code> is <code>False</code> and <code>not False</code> is <code>True</code>. Here are some examples: <syntaxhighlight lang=python> >>> not False True >>> not True False >>> True and True True >>> True and False False >>> True or False True >>> False or False False >>> not(False or False) True >>> not(False and False) True >>> not(False and True) True </syntaxhighlight> All of the possible combinations are: <syntaxhighlight lang=python> True and True: True True and False: False False and True: False False and False: False True or True: True True or False: True False or True: True False or False: False (not(True and True)) == ((not True) or (not True)): True (not(True and False)) == ((not True) or (not False)): True (not(False and True)) == ((not False) or (not True)): True (not(False and False)) == ((not False) or (not False)): True (not(True or True)) == ((not True) and (not True)): True (not(True or False)) == ((not True) and (not False)): True (not(False or True)) == ((not False) and (not True)): True (not(False or False)) == ((not False) and (not False)): True </syntaxhighlight> The above negated statements reflect [https://en.wikipedia.org/wiki/De_Morgan%27s_laws#Engineering "De Morgan's laws."] For example, the statement <syntaxhighlight lang=python> (not(True and True)) == ((not True) or (not True)): True </syntaxhighlight> is equivalent to: {{overline|True and True}} <math>\equiv</math> {{overline|True}} or {{overline|True}}. ==A simple way to choose one of two possible values:== <syntaxhighlight lang=python> >>> L1 = [1,2,0,3,0,5] </syntaxhighlight> Produce list L2, a copy of L1, except that each value 0 in L1 has been replaced by 0xFF: <syntaxhighlight lang=python> >>> L2 = [] >>> >>> for p in L1 : ... L2 += ([p], [0xFF])[p == 0] ... >>> L2 [1, 2, 255, 3, 255, 5] >>> </syntaxhighlight> ==Expressions containing multiple booleans== Consider the expression: <syntaxhighlight lang=python> A and B or C </syntaxhighlight> Does this mean <syntaxhighlight lang=python> (A and B) or C </syntaxhighlight> Does it mean <syntaxhighlight lang=python> A and (B or C) </syntaxhighlight> It might be tempting to say that there is no difference, but look closely: <syntaxhighlight lang=python> for A in True, False : for B in True, False : for C in True, False : b1 = (A and B) or C b2 = A and (B or C) if b1 != b2 : print ( ''' for A = {}, B = {}, C = {} (A and B) or C = {} A and (B or C) = {} '''.format(A, B, C, b1, b2) ) </syntaxhighlight> <pre> for A = False, B = True, C = True (A and B) or C = True A and (B or C) = False for A = False, B = False, C = True (A and B) or C = True A and (B or C) = False </pre> Add another boolean to the expression: <syntaxhighlight lang=python> A and B or C and D </syntaxhighlight> and the number of different possibilities is at least 96. You can see that the complexity of these expressions quickly becomes unmanageable. The essence of this section: Keep your expressions simple and use parentheses as necessary to ensure that your code is interpreted exactly as you expect. {{RoundBoxBottom}} =Complex Numbers= {{RoundBoxTop|theme=2}} A [[Wikipedia:Complex number|complex number]] is represented as <code>a+bi</code> where <code>a</code> and b are real numbers, like 7 or 12, and <code>i</code> is an [[Wikipedia:Imaginary number|imaginary number]], where <code>i² = -1</code>. In the computer field, and in the world of Python, <code>i</code> is denoted as <code>j</code> for technical reasons, so we use <code>a+bj</code>. It should also be noted that <code>a</code> and <code>b</code> are '''both''' treated as floats. This subject will be briefly covered until later lessons. <syntaxhighlight lang=python> >>> 1+2j (1+2j) >>> -1+5.5j (-1+5.5j) >>> 0+5.5j 5.5j >>> 2j 2j >>> 1+0j (1+0j) >>> complex(3,-2) (3-2j) </syntaxhighlight> Note also that j cannot be used on its own without b. If you try to use j on its own, Python will look for a variable <code>j</code> and use the value of that variable, or report an error if the variable is not known or a wrong type. So the imaginary number i or j must always be written as 1j. <syntaxhighlight lang=python> >>> a = 5 + 3j >>> a - j Traceback (most recent call last): File "<stdin>", line 1, in <module> NameError: name 'j' is not defined >>> a - 1j (5+2j) >>> j = -3j >>> a - j (5+6j) >>> a - 1j (5+2j) </syntaxhighlight> The last result illustrates that even when the variable j has a numerical value, 1j (where, as above, can be any number) is always interpreted as the imaginary number j, not the variable j. The usual mathematical operations can be performed on complex numbers: <syntaxhighlight lang=python> >>> (1+3j)+(2-5j) (3-2j) >>> (1+3j)-(2-5j) (-1+8j) >>> (1+3j)*(2-5j) (17+1j) >>> a = complex(3,-5) ; b = 1 ; b += 2j ; a ; b (3-5j) (1+2j) >>> a + b ; a - b (4-3j) (2-7j) >>> a * b ; a / b (13+1j) (-1.4-2.2j) >>> a + 4 ; b - 2j ; a * 3.1 ; b / 2 (7-5j) (1+0j) (9.3-15.5j) (0.5+1j) >>> b ; b /= 5 ; b (1+2j) (0.2+0.4j) >>> a = complex(3,-5j) ; a (8-0j) </syntaxhighlight> Look closely at the last example. It does not produce an error, but is it what you want? {{Note|'''Note:''' the imaginary number, <code>j</code>, isn't case-sensitive, so you can use <code>j</code> or <code>J</code>.}} You can extract the real number and the imaginary number by using <code>.real</code> and <code>.imag</code> respectively. <syntaxhighlight lang=python> >>> (1+2j).real 1.0 >>> (1+2j).imag 2.0 >>> var = 5+3j >>> var.real 5.0 >>> var.imag 3.0 </syntaxhighlight> {{Note|'''Note:'''You'll get '''weird''' results if you '''don't''' use parentheses on a real number that '''isn't''' stored in a variable.}} ==[https://docs.python.org/3/library/cmath.html?highlight=complex#module-cmath cmath] — Mathematical functions for complex numbers== </br> ===Introduction=== {{RoundBoxTop|theme=2}} [[File:20180311Complex.png|thumb|400px|''' Figure 1: Components of complex number Z.''' </br></br> Origin at point <math>(0,0)</math>.</br> <math>Z.real</math> parallel to <math>X</math> axis.</br> <math>Z.imag</math> parallel to <math>Y</math> axis.</br> <math>r = abs(Z)</math></br> <math>Z = r(\cos\phi + 1j*\sin \phi) = Z.real + 1j*Z.imag</math> ]] A Python complex number <code>Z</code> is stored internally using rectangular or Cartesian coordinates. It is completely determined by its real part <code>Z.real</code> and its imaginary part <code>Z.imag</code>. See Figure 1. In Cartesian Geometry of 2 dimensions the real part of complex number <code>Z</code> is parallel to the <math>X</math> axis and the imaginary part is parallel to the <math>Y</math> axis. The <code>modulus</code> of <code>Z</code> is the line from origin to <code>Z</code> with length <code>r</code>. In scientific notation the number <code>Z</code> is written as <math>a + bi</math> where <math>i = \sqrt{-1}.</math> Within Python <code>Z</code> is written as <code>(a + bj).</code> '''Note:''' Because the expression 'bj' could be the name of a variable, and to avoid confusion, it might be better to express a complex number within Python as <code>(a + b*1j)</code>. The values <code>a,b</code> are the rectangular coordinates of complex number <code>(a + bj)</code>. <syntaxhighlight lang=python> >>> Z = complex(3.6, 2.7) ; Z (3.6+2.7j) >>> Z = 3.6 + 2.7j ; Z (3.6+2.7j) >>> Z = 3.6 + 2.7J ; Z # 'J' upper case. (3.6+2.7j) >>> Z.real ; Z.imag 3.6 2.7 >>> >>> Z.real + 1j*Z.imag (3.6+2.7j) >>> Z.real + 1j*Z.imag == Z True >>> </syntaxhighlight> The absolute value of a complex number is the length of the modulus: <math>r = \sqrt{Z.real^2 + Z.imag^2}</math> <syntaxhighlight lang=python> >>> abs(Z) 4.5 >>> (Z.real**2 + Z.imag**2)**(1/2) 4.5 >>> </syntaxhighlight> Some useful [https://docs.python.org/3/library/cmath.html?highlight=complex#constants constants]: <syntaxhighlight lang=python> >>> import cmath >>> ε = cmath.e ; ε # Greek epsilon, base of natural logarithms. 2.718281828459045 >>> π = cmath.pi ; π # Greek pi. 3.141592653589793 >>> τ = cmath.tau ; τ # Greek tau. 6.283185307179586 >>> τ == 2*π >>> True </syntaxhighlight> ====Addition of complex numbers==== {{RoundBoxTop|theme=2}} To add two complex numbers in rectangular format, simply add the real parts, then the imaginary parts: <syntaxhighlight lang=python> >>> import cmath >>> >>> cn1 = 1+3j ; cn1 (1+3j) >>> cn2 = 2-5j ; cn2 (2-5j) >>> cn1 + cn2 == cn1.real + cn2.real + 1j*(cn1.imag + cn2.imag) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} ===Polar coordinates=== Polar coordinates provide an alternative way to represent a complex number. In polar coordinates, a complex number <code>Z</code> is defined by the <code>modulus r</code> and the <code>phase angle φ (phi)</code>. The modulus <code>r</code> is <code>abs(Z)</code> as above, while the phase <code>φ</code> is the counterclockwise angle, measured in radians, from the positive x-axis to the line segment that joins the origin to <code>Z</code>. <math>\tan \phi = \frac{Z.imag}{Z.real}.</math> <syntaxhighlight lang=python> >>> tan_phi = Z.imag/Z.real ; tan_phi 0.75 >>> φ = cmath.atan(tan_phi).real ; φ 0.6435011087932844 # φ in radians >>> φ * (180/π) 36.86989764584402 # φ in degrees. >>> </syntaxhighlight> Class method [https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.phase <code>cmath.phase(Z)</code>] returns the phase: <syntaxhighlight lang=python> >>> φ1 = cmath.phase(Z) ; φ1 0.6435011087932844 >>> φ1 == φ True >>> </syntaxhighlight> From figure 1: <math>\cos \phi = \frac{Z.real}{r};\ Z.real = r \cos \phi.</math> <math>\sin \phi = \frac{Z.imag}{r};\ Z.imag = r \sin \phi.</math> If polar coordinates are known: <math>Z = r \cos \phi + 1j * r \sin \phi = r (\cos \phi + 1j * \sin \phi).</math> <syntaxhighlight lang=python> >>> Z ; r ; φ (3.6+2.7j) 4.5 0.6435011087932844 >>> >>> cosφ = Z.real / r ; cosφ 0.8 >>> sinφ = Z.imag / r ; sinφ 0.6 >>> >>> Z1 = r*( cosφ + 1j*sinφ ) ; Z1 (3.6+2.7j) >>> </syntaxhighlight> ====De Moivre's formula==== The format containing polar coordinates is useful [https://en.wikipedia.org/wiki/De_Moivre%27s_formula because]: <math>Z^n = r^n(\cos(n\phi) + i\sin(n\phi))</math> =====Z^2===== {{RoundBoxTop|theme=2}} <math>Z^2 = r^2(\cos(2\phi) + i\sin(2\phi))</math> ======Proof====== {{RoundBoxTop|theme=2}} <math>Z = r(\cos\phi + i\sin\phi)</math> <math>Z^2 = (r(\cos\phi + i\sin\phi))^2</math> <math>Z^2 = r^2(\cos\phi + i\sin\phi)^2</math> <math>Z^2 = r^2(\cos^2\phi + 2i\sin\phi\cos\phi - \sin^2\phi)</math> <math>Z^2 = r^2(\cos^2\phi - \sin^2\phi + 2i\sin\phi\cos\phi)</math> <math>Z^2 = r^2(\cos(2\phi) + i\sin(2\phi))</math> {{RoundBoxBottom}} ======An example====== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> >>> sin2φ = cmath.sin(2*φ).real ; sin2φ 0.96 >>> cos2φ = cmath.cos(2*φ).real ; cos2φ 0.28 >>> Z (3.6+2.7j) >>> Z**2 (5.67+19.44j) >>> r*r*(cos2φ + 1J*sin2φ) (5.67+19.44j) >>> </syntaxhighlight> {{RoundBoxBottom}} ======Z and Z^2 on polar diagram====== {{RoundBoxTop|theme=2}} [[File:ZandZ^2onPolarDiagram1.png|thumb|400px|''' Figure 2: Z and Z^2.''' </br></br> <math>abs(Z_1) = abs(Z_2) = r_1 = r_2</math>.</br> Phase of <math>Z_1 = \phi</math>. Phase of <math>Z_2 = 180 + \phi</math>.</br> <math>Z_2 = -Z_1</math>.</br> <math>abs(Z) = r = r_1^2</math>. Phase of <math>Z = 2\phi</math>.</br> <math>Z = Z_1^2 = Z_2^2</math>.</br> ]] In Figure 2 <math>Z_1 = 3 + 1j*\frac{5}{4}</math>. <math>Z_2 = -3 + 1j*(-\frac{5}{4})</math> <math>= -3 - 1j*\frac{5}{4}</math> <math>= -(3 + 1j*\frac{5}{4}) = -Z_1.</math> <math>r_1</math> = length <math>OZ_1</math> = abs<math>(Z_1) = r_2</math> = length <math>OZ_2</math> = abs<math>(Z_2) = \frac{13}{4}.</math> <math></math><math></math><math></math><math></math> Angle <math>\phi</math> is the phase of <math>Z_1.\ \cos \phi = \frac{12}{13}.\ \sin \phi = \frac{5}{13}</math>. <math>Z_1 = r_1*(\cos \phi + 1j* \sin \phi)</math> <math>= \frac{13}{4}*(\frac{12}{13} + 1j*\frac{5}{13})</math> <math>= 3 + 1j*\frac{5}{4}.</math> <math>r</math> = length <math>OZ</math> = abs<math>(Z) = r_1^2 = \frac{169}{16}.</math> Phase of <math>Z = 2\phi.</math> Therefore: <math>Z = Z_1^2 = Z_2^2.</math> <math>\sin 2\phi = 2\sin\phi\cos\phi</math> <math>= 2(\frac{5}{13})(\frac{12}{13})</math> <math>= \frac{120}{169}.</math> <math>\cos 2\phi = \cos^2\phi - \sin^2\phi</math> <math>= (\frac{12}{13})(\frac{12}{13}) - (\frac{5}{13})(\frac{5}{13})</math> <math>= \frac{144-25}{169}</math> <math>= \frac{119}{169}.</math> <math>Z = r*(\cos 2\phi + 1j*\sin 2\phi)</math> <math>= \frac{169}{16}(\frac{119}{169} + 1j*\frac{120}{169})</math> <math>= \frac{119}{16} + 1j*\frac{120}{16}</math> <math>= 7\frac{7}{16} + 1j*7\frac{1}{2}.</math> <syntaxhighlight lang=python> >>> Z1 = 3+1j*(5/4) ; Z1 ; abs(Z1) ; abs(Z1) == 13/4 (3+1.25j) 3.25 True >>> Z = Z1*Z1 ; Z ; Z.real == 7+(7/16) (7.4375+7.5j) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} =====\sqrt{Z}===== ------------------------------- <math>\sqrt{Z} = \sqrt{r}(\cos(\phi/2) + i\sin(\phi/2))</math> <syntaxhighlight lang=python> >>> sinφ_2 = cmath.sin(φ/2).real ; sinφ_2 0.31622776601683794 >>> cosφ_2 = cmath.cos(φ/2).real ; cosφ_2 0.9486832980505138 >>> Z (3.6+2.7j) >>> cmath.sqrt(Z) (2.0124611797498106+0.670820393249937j) >>> (r**0.5)*(cosφ_2 + 1J*sinφ_2) (2.0124611797498106+0.6708203932499369j) >>> </syntaxhighlight> ======\sqrt{1}====== {{RoundBoxTop|theme=2}} <math>\cos(0) + 1j*\sin(0) = 1 + 1j*0 = 1</math> <math>\sqrt{1} = \sqrt{\cos(0) + 1j*\sin(0)}</math> <math>= \cos(0/2) + 1j*\sin(0/2)</math> <math>= \cos(0) + 1j*\sin(0) = 1</math> Trigonometric functions are cyclical: <math>\cos(360) + 1j*\sin(360) = 1 + 1j*0 = 1</math> <math>\sqrt{1} = \sqrt{\cos(360) + 1j*\sin(360)}</math> <math>= \cos(360/2) + 1j*\sin(360/2)</math> <math>= \cos(180) + 1j*\sin(180) = -1 + 1j*0 = -1</math> The two square roots of <code>1</code> are <code>1</code> and <code>-1.</code> <syntaxhighlight lang=python> >>> 1**2 ; (-1)**2 1 1 >>> </syntaxhighlight> {{RoundBoxBottom}} ======\sqrt{-1}====== {{RoundBoxTop|theme=2}} <math>\cos(180) + 1j*\sin(180) = -1 + 1j*0 = -1</math> <math>\sqrt{-1} = \sqrt{\cos(180) + 1j*\sin(180)}</math> <math>= \cos(180/2) + 1j*\sin(180/2)</math> <math>= \cos(90) + 1j*\sin(90) = 0 + 1j*1 = 1j</math> Trigonometric functions are cyclical: <math>\cos(180+360) + 1j*\sin(180+360) = -1 + 1j*0 = -1</math> <math>\sqrt{-1} = \sqrt{\cos(180+360) + 1j*\sin(180+360)}</math> <math>= \cos(90+180) + 1j*\sin(90+180)</math> <math>= \cos(270) + 1j*\sin(270) = 0 + 1j*(-1) = -1j</math> The two square roots of <code>-1</code> are <code>1j</code> and <code>-1j.</code> <syntaxhighlight lang=python> >>> (1j)**2 ; (-1j)**2 (-1+0j) (-1+0j) >>> </syntaxhighlight> {{RoundBoxBottom}} =====Cube roots of 1 simplified===== {{RoundBoxTop|theme=2}} <math>\cos(0) + 1j*\sin(0) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(0) + 1j*\sin(0))^{(1/3)}</math> <math>= \cos(0/3) + 1j*\sin(0/3)</math> <math>= \cos(0) + 1j*\sin(0) = 1</math> Trigonometric functions are cyclical: <math>\cos(360) + 1j*\sin(360) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(360) + 1j*\sin(360))^{(1/3)}</math> <math>= \cos(360/3) + 1j*\sin(360/3)</math> <math>= \cos(120) + 1j*\sin(120) = -\cos(60) + 1j*\sin(60) </math> <math>= -\frac{1}{2} + 1j\frac{\sqrt{3}}{2} = \frac{-1 + 1j*\sqrt{3}}{2}</math> Proof: <math>r_2 = -1(\cos(60) - 1J*\sin(60)) = -1(\cos(-60) + 1J*\sin(-60)).</math> <math>r_2^3 = (-1)^3(\cos(-180) + 1J*\sin(-180)) = -1(-1 + 1J*0) = 1.</math> <math>\cos(720) + 1j*\sin(720) = 1 + 1j*0 = 1</math> <math>\sqrt[3]{1} = (\cos(720) + 1j*\sin(720))^{(1/3)}</math> <math>= \cos(720/3) + 1j*\sin(720/3)</math> <math>= \cos(240) + 1j*\sin(240) = -\cos(60) - 1j*\sin(60) </math> <math>= -\frac{1}{2} - 1j\frac{\sqrt{3}}{2} = \frac{-1 - 1j*\sqrt{3}}{2}</math> Proof: <math>r_3 = -1(\cos(60) + 1J*\sin(60))</math>. <math>r_3^3 = (-1)^3(\cos(180) + 1J*\sin(180)) = -1(-1 + 1J*0) = 1.</math> The three cube roots of 1 are : <math>1, -\cos 60^\circ \pm 1j*\sin 60^\circ</math> or <math>1,\ \frac{-1 + 1j*\sqrt{3}}{2},\ \frac{-1 - 1j*\sqrt{3}}{2}.</math> <syntaxhighlight lang=python> >>> r1 = 1 ; v1 = r1**3 ; v1 1 >>> r2 = ( -1 + 1j * (3**0.5)) / 2 ; v2 = r2**3 ; v2 (0.9999999999999998+1.1102230246251565e-16j) >>> r3 = ( -1 - 1j * (3**0.5)) / 2 ; v3 = r3**3 ; v3 (0.9999999999999998-1.1102230246251565e-16j) >>> >>> [ cmath.isclose(v,1,abs_tol=1e-15) for v in (v1,v2,v3) ] [True, True, True] >>> </syntaxhighlight> {{RoundBoxBottom}} ====Multiplication of complex numbers==== {{RoundBoxTop|theme=2}} To multiply two complex numbers in polar format, multiply the moduli and add the phases. <syntaxhighlight lang=python> >>> cn1 = 3+4j ; cn1 (3+4j) >>> r1,φ1 = cmath.polar(cn1) ; r1 ; φ1 5.0 0.9272952180016122 # radians >>> >>> cn2 = -4+3j ; cn2 (-4+3j) >>> r2,φ2 = cmath.polar(cn2) ; r2 ; φ2 5.0 2.498091544796509 # radians >>> >>> v1 = cn1*cn2 ; v1 (-24-7j) >>> v2 = 25*( cmath.cos(φ1 + φ2) + 1j*cmath.sin(φ1 + φ2) ) ; v2 # r1 * r2 = 25 (-24-7.000000000000002j) >>> >>> cmath.isclose(v1, v2, abs_tol=1e-15) True >>> </syntaxhighlight> =====Proof===== <math>(\cos A + 1j*\sin A)*(\cos B + 1j*\sin B)</math> <math>= \cos A \cos B + 1j*\cos A \sin B + 1j*\sin A \cos B + j^2\sin A\sin B</math> <math>= \cos A \cos B - \sin A\sin B + 1j*(\cos A \sin B + \sin A \cos B) </math> <math>= \cos(A + B) + 1j*\sin(A + B)</math> {{RoundBoxBottom}} ===Classification functions=== ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.isclose cmath.isclose(a, b, *, rel_tol=1e-09, abs_tol=0.0)]==== Return True if the values a and b are close to each other and False otherwise. Whether or not two values are considered close is determined according to given absolute and relative tolerances. <syntaxhighlight lang=python> >>> v1; cmath.polar(v1) (87283949+87283949j) (123438144.45328155, 0.7853981633974483) >>> v2; cmath.polar(v2) (87283949+87283950j) (123438145.16038834, 0.7853981691258783) >>> cmath.isclose(v1,v2) False >>> >>> cmath.isclose(v1,v2, rel_tol=8e-9) False >>> cmath.isclose(v1,v2, rel_tol=9e-9) True >>> >>> cmath.isclose(v1,v2, abs_tol=1) True >>> cmath.isclose(v1,v2, abs_tol=.5) False >>> </syntaxhighlight> The following python code implements this functionality with a list or tuple of numbers as input. {{RoundBoxTop|theme=4}} <syntaxhighlight lang=python> # python code import decimal D = decimal.Decimal allEqualDebug = 0 def allEqual(values, tolerance=1e-15) : ''' status = allEqual(values[, tolerance]) status may be: True, False or None. To check for "close to zero", include 0 in values: status = allEqual(list(values)+[0] [, tolerance]) ''' if type(values) not in (tuple,list) : print ('allEqual()1:', type(values), 'not in (tuple,list)') return None if len(values) < 2 : print ('allEqual()2: Must have >= 2 values to compare.') return None if type(tolerance) not in (float,D,complex) : print ('allEqual()3:', type(tolerance), 'not in (float,Decimal,complex)') return None tolerance = abs (tolerance) zeroInValues = (0 in values) for v in values : if type (v) not in (int,float,complex,D) : print ('allEqual()4:', type(v), 'not in (int,float,complex,Decimal)') return None set1 = set(values) - {0} if zeroInValues : for v in set1 : if abs(v) > tolerance : if allEqualDebug: print ('allEqual()5: value not close to 0.', v ) return False return True values = [] for v in set1 : if type(v) in (int,D) : values += [float(v)] else : values += [v] # All values are float or complex and non-zero without duplicates. for p in range (0, len(values)) : for q in range (p+1, len(values)) : a = values[p] ; b = values[q] v1,v2 = abs(a-b) , tolerance*abs((a+b)/2) # tolerance is relative value. if v1 > v2 : if allEqualDebug: print ('allEqual()6: 2 values not close.', a,',',b ) print (' abs(a-b) =', v1) print (' comparison =', v2) return False return True </syntaxhighlight> The above test for "approximately equal" is: <code>abs(a-b) <= tolerance*abs((a+b)/2).</code> This test works for floating point numbers, complex numbers or a mixture of both. It also ensures that 2 not-equal complex numbers of same absolute value (<code>3+4j, 4+3j</code> for example) fail the test. With this algorithm, 2 small numbers (<code>1.23456e-17, -1.23456e-17</code> for example) both pass the test for "close to 0," but fail the test for "approximately equal." {{RoundBoxBottom}} ===Power and logarithmic functions=== ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.sqrt cmath.sqrt(x)]==== {{RoundBoxTop|theme=2}} Return the square root of <code>x.</code> <syntaxhighlight lang=python> >>> cmath.sqrt(-1) 1j >>> >>> cmath.sqrt(7+24j) (4+3j) >>> -cmath.sqrt(7+24j) (-4-3j) # sqrt has both positive and negative values. >>> (-cmath.sqrt(7+24j))**2 (7+24j) >>> >>> cmath.sqrt(7+(7/16) + 1j*7.5) (3+1.25j) >>> </syntaxhighlight> {{RoundBoxBottom}} ====[https://docs.python.org/3/library/cmath.html?highlight=complex#cmath.exp cmath.exp(x)]==== {{RoundBoxTop|theme=2}} Return the exponential value <code>e**x</code>. <syntaxhighlight lang=python> >>> cmath.exp(1) (2.718281828459045+0j) # Value of e, base of natural logarithms. >>> </syntaxhighlight> [https://en.wikipedia.org/wiki/Euler%27s_formula Euler's formula:] <math>e^{i \theta} = \cos\theta + 1j*\sin\theta</math> When <math>\theta</math> has the value <math>\frac{\pi}{3}</math> or <math>60</math> degrees: <syntaxhighlight lang=python> >>> π = cmath.pi ; π 3.141592653589793 >>> >>> cmath.exp(1j*π/3) # π/3 = 60 degrees. (0.5+0.8660254037844386j) >>> >>> cmath.cos(π/3) (0.5-0j) >>> cmath.sin(π/3) (0.8660254037844386+0j) >>> >>> cmath.exp(1j*π/3) == cmath.cos(π/3) + 1j*cmath.sin(π/3) True >>> </syntaxhighlight> The case when <math>\theta = \pi</math>: <syntaxhighlight lang=python> >>> cmath.exp(1j*π) (-1+0j) >>> </syntaxhighlight> The combination of value <code>-1</code> and expression <code>cmath.exp(1j*π)</code> is equivalent to [https://en.wikipedia.org/wiki/Euler%27s_identity Euler's famous Identity]: <math>e^{i \pi} = -1</math> =====When <code>x</code> is complex:===== {{RoundBoxTop|theme=2}} According to the [https://en.wikipedia.org/wiki/Exponentiation#Imaginary_exponents_with_base_e rules of exponents], the expression <code>cmath.exp(a+bj)</code> is equivalent to: <math>e^{(a+bj)} = e^ae^{bj} = e^a(\cos b + 1j*\sin b)</math> <math>e^{(1+1j*\pi)} = e^1e^{1j*\pi} = e(-1)</math> <syntaxhighlight lang=python> >>> e = cmath.exp(1) ; e (2.718281828459045+0j) >>> >>> b = cmath.exp(1j*π) ; b (-1+1.2246467991473532e-16j) >>> cmath.isclose(b.imag,0,abs_tol=1e-15) True >>> b=complex(b.real,0);b (-1+0j) >>> >>> c = cmath.exp(1+1j*π) ; c (-2.718281828459045+3.328935140402784e-16j) >>> cmath.isclose(c.imag,0,abs_tol=1e-15) True >>> c=complex(c.real,0);c (-2.718281828459045+0j) >>> >>> c == e*b == e*(-1) True >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} =Number Conversions= {{RoundBoxTop|theme=3}} ==Introduction== {{RoundBoxTop|theme=2}} Since integers and floats can't be mixed together in some situations, you'll need to be able to convert them from one type to another. Luckily, it's very easy to perform a conversion. To convert a data type to an integer, use the <code>int()</code> function. <syntaxhighlight lang=python> >>> int(1.5) 1 >>> int(10.0) 10 >>> int(True) 1 >>> int(False) 0 >>> int('0xFF', base=16) ; int('0xF1F0', 16) ; int('0b110100111', 0) ; int('11100100011',2) 255 61936 423 1827 </syntaxhighlight> You can even convert strings, which you'll learn about later. <syntaxhighlight lang=python> >>> int("100") 100 </syntaxhighlight> To convert a data type to a float, use the <code>float()</code> function. Like the integer, you can convert strings to floats. <syntaxhighlight lang=python> >>> float(102) 102.0 >>> float(932) 932.0 >>> float(True) 1.0 >>> float(False) 0.0 >>> float("101.42") 101.42 >>> float("4") 4.0 </syntaxhighlight> {{Note|'''Note''': You cannot use any of the above conversions on a complex number, as it will raise an error. You can work around this by using <code>.real</code> and <code>.imag</code>}} You can also use the <code>bool()</code> function to convert a data type to a Boolean. <syntaxhighlight lang=python> >>> bool(1) True >>> bool(0) False >>> bool(0.0) False >>> bool(0.01) True >>> bool(14) True >>> bool(14+3j) True >>> bool(3j) True >>> bool(0j) False >>> bool("") False >>> bool("Hello") True >>> bool("True") True >>> bool("False") True </syntaxhighlight> {{Note|'''Note:''' Notice that <code>bool("False")</code> is <code>True</code>. Unlike <code>int()</code> and <code>float()</code>, when <code>bool()</code> converts a string, it checks to see if the string is empty or not.}} Converting a data type to a complex is a little more tricky, but still easy. All you need to do is use the function <code>complex()</code> which takes two parameters, one of which is optional. The first parameter is the real number, which is required, and the second parameter is the imaginary number, which is optional. <syntaxhighlight lang=python> >>> complex(True) (1+0j) >>> complex(False) 0j >>> complex(3, 1) (3+1j) >>> complex(1, 22/7) (1+3.142857142857143j) >>> complex(0, 1.5) 1.5j >>> complex(7, 8) (7+8j) >>> complex("1") (1+0j) >>> complex("1+4j") (1+4j) >>> complex("9.75j") 9.75j </syntaxhighlight> {{RoundBoxBottom}} ==Converting integers, decimal to non-decimal== {{RoundBoxTop|theme=2}} This conversion is from int to str representing int: <syntaxhighlight lang=python> >>> a = 12345678901234567890 >>> b = bin(a) ; b '0b1010101101010100101010011000110011101011000111110000101011010010' >>> h = hex(a) ; h '0xab54a98ceb1f0ad2' >>> o = oct(a) ; o '0o1255245230635307605322' >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting integers, non-decimal to decimal== {{RoundBoxTop|theme=2}} This conversion is from str representing int to int: <syntaxhighlight lang=python> >>> a;b;h;o 12345678901234567890 '0b1010101101010100101010011000110011101011000111110000101011010010' '0xab54a98ceb1f0ad2' '0o1255245230635307605322' >>> >>> int(b,base=0) == int(b,base=2) == int(b,0) == int(b,2) == a # Base 0 or correct base is required. True >>> int(h,16) == a True >>> int(o,8) == a True >>> >>> int ('ab54a98ceb1f0ad2', 16) == a # When base 16 is supplied, the prefix '0x' is not necessary. True >>> >>> eval(b) == a # Function eval(...) provides simple conversion from str to base type. True >>> eval(h) == a True >>> eval(o) == a True >>> >>> int('12345678901234567890',0) == int('12345678901234567890',base=0) == a True >>> int('12345678901234567890',10) == int('12345678901234567890',base=10) == a True >>> eval('12345678901234567890') == int('12345678901234567890') == a True >>> </syntaxhighlight> {{RoundBoxBottom}} ==Interfacing with Python's Decimal module== {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> >>> from decimal import * >>> float1 = 3.14159 >>> dec1 = Decimal(float1) ; dec1 Decimal('3.14158999999999988261834005243144929409027099609375') >>> str(dec1) '3.14158999999999988261834005243144929409027099609375' >>> >>> float2 = eval(str(dec1)) ; float2 3.14159 >>> isinstance(float2, float) True >>> float2 == float1 True >>> >>> float2 = float(dec1) ; float2 3.14159 >>> isinstance(float2, float) True >>> float2 == float1 True >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting <code>int</code> to <code>bytes</code>== {{RoundBoxTop|theme=2}} Method <code>int.'''to_bytes'''(length, byteorder, *, signed=False)</code> returns a bytes object representing an integer where: <pre> length (in bytes) must be sufficient to contain int, at least (int.bit_length() + 7) // 8 byteorder can be 'big', 'little' or sys.byteorder, signed must be True if int is negative. </pre> For example: <syntaxhighlight lang=python> >>> int1 = 0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big') ; bytes1 b'\x12\x05' # A bytes object containing int1. >>> isinstance(bytes1, bytes) True >>> >>> int2 = 0xe205 >>> bytes2 = int2.to_bytes(2, byteorder='big', signed=True) ; bytes2 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> >>> bytes2 = int2.to_bytes(3, byteorder='big', signed=True) ; bytes2 b'\x00\xe2\x05' >>> >>> bytes2 = int2.to_bytes(2, byteorder='big') ; bytes2 b'\xe2\x05' >>> >>> int3 = -7675 >>> bytes3 = int3.to_bytes(2, byteorder='big') ; bytes3 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: can't convert negative int to unsigned >>> >>> bytes3 = int3.to_bytes(2, byteorder='big', signed=True) ; bytes3 b'\xe2\x05' >>> >>> bytes2 == bytes3 True >>> </syntaxhighlight> The bytes object <code>b'\xe2\x05'</code> can represent 0xe205 or -7675 depending on whether it's interpreted as signed or unsigned. To preserve the original int, let <code>length = ((int.bit_length() + 7) // 8) + 1</code> if necessary and use signed=True. <syntaxhighlight lang=python> >>> hex(int2); hex(int3) '0xe205' '-0x1dfb' >>> bytes2 = int2.to_bytes(3, byteorder='big', signed=True) ; bytes2 b'\x00\xe2\x05' # Most significant bit (value=0) preserves sign (+). >>> bytes3 = int3.to_bytes(2, byteorder='big', signed=True) ; bytes3 b'\xe2\x05' # Most significant bit (value=1) preserves sign (-). >>> </syntaxhighlight> {{RoundBoxBottom}} ==Converting <code>bytes</code> to <code>int</code>== {{RoundBoxTop|theme=2}} A bytes object is an immutable sequence with every member <math>x</math> an int satisfying 0xFF <math>>= x >= 0.</math> The classmethod <code>int.from_bytes(bytes, byteorder, *, signed=False)</code> may be used to convert from bytes object to int. The value returned is an int represented by the given bytes object or any sequence convertible to bytes object: <syntaxhighlight lang=python> >>> hex(int.from_bytes(b'\xcd\x34', byteorder='little')) '0x34cd' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='big')) '0xcd34' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='little', signed=True)) '0x34cd' >>> hex(int.from_bytes(b'\xcd\x34', byteorder='big', signed=True)) '-0x32cc' >>> hex(int.from_bytes([0xCD,0x34], byteorder='big')) # Input is list convertible to bytes. '0xcd34' >>> hex(int.from_bytes((0xCD,0x34), byteorder='big')) # Input is tuple convertible to bytes. '0xcd34' >>> hex(int.from_bytes({0xCD,0x34}, byteorder='big')) '0x34cd' # Ordering of set is unpredictable. >>> hex(int.from_bytes(bytes([0xCD,0x34]), byteorder='big')) # Input is bytes object. '0xcd34' >>> hex(int.from_bytes(bytearray([0xCD,0x34]), byteorder='big')) # Input is bytearray. '0xcd34' >>> </syntaxhighlight> ===Complete conversion=== Complete conversion means conversion from int to bytes to int, or from bytes to int to bytes. When converting int/bytes/int, it is reasonable to expect that the final int should equal the original int. If you keep byteorder consistent and signed=True, you will produce consistent results: Positive number with msb (most significant bit) clear: <syntaxhighlight lang=python> >>> int1 = 0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 b'\x12\x05' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '0x1205' >>> int1==int1a True </syntaxhighlight> Negative number with msb clear: <syntaxhighlight lang=python> >>> int1 = -0x1205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 b'\xed\xfb' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '-0x1205' >>> int1==int1a True </syntaxhighlight> Positive number with msb set: <syntaxhighlight lang=python> >>> int1 = 0xF205 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> bytes1 = int1.to_bytes(3, byteorder='big', signed=True) ; bytes1 b'\x00\xf2\x05' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '0xf205' >>> int1==int1a True </syntaxhighlight> Negative number with msb set: <syntaxhighlight lang=python> >>> int1 = -0xF305 >>> bytes1 = int1.to_bytes(2, byteorder='big', signed=True) ; bytes1 Traceback (most recent call last): File "<stdin>", line 1, in <module> OverflowError: int too big to convert >>> bytes1 = int1.to_bytes(3, byteorder='big', signed=True) ; bytes1 b'\xff\x0c\xfb' >>> int1a = int.from_bytes(bytes1, byteorder='big', signed=True) ; hex(int1a) '-0xf305' >>> int1==int1a True </syntaxhighlight> {{RoundBoxBottom}} ==floats== {{RoundBoxTop|theme=2}} Two methods support conversion to and from hexadecimal strings. Because Python’s floats are stored internally as binary numbers, converting a float to or from a decimal string usually involves a small rounding error. In contrast, hexadecimal strings allow exact representation and specification of floating-point numbers. ===from hex=== {{RoundBoxTop|theme=3}} A hexadecimal float as represented by a hexadecimal string and similar to decimal floats can be int, point float or exponent float. A point float contains a decimal point and at least one hex digit. It may contain an exponent represented by <code>p</code> and a power of 2. An exponent float contains at least one hex digit and exponent. Class method <code>float.fromhex(s)</code> returns the float represented by hexadecimal string <code>s</code>. The string <code>s</code> may have leading and trailing whitespace. <syntaxhighlight lang=python> >>> float.fromhex(' ABC ') ; 0xABC 2748.0 2748 >>> float.fromhex(' 0xABCp6 ') ; 0xABC *(2**6) # Within the string ' 0xABCp6 ' the prefix '0x' is optional. 175872.0 175872 >>> float.fromhex(' ABCp-5 ') ; 0xABC *(2**(-5)) 85.875 85.875 >>> </syntaxhighlight> ====point float==== Consider <code>f1 = float.fromhex('0x3.a7d4')</code>. f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} + \frac{0xD}{16^3} + \frac{0x4}{16^4})</math> To simplify the conversion put the hex string in the format of exponent float without decimal point: f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} + \frac{0xD}{16^3} + \frac{0x4}{16^4})(16^4)(16^{-4})</math> f1 = <math>(3(16^4) + \frac{0xA(16^4)}{16} + \frac{0x7(16^4)}{16^2} + \frac{0xD(16^4)}{16^3} + \frac{0x4(16^4)}{16^4})(16^{-4})</math> f1 = <math>(0x30000 + 0xA000 + 0x700 + 0xD0 + 0x4)(16^{-4})</math> f1 = <math>(0x3A7D4)(16^{-4}) = 0x3A7D4(2^{-16})</math> <syntaxhighlight lang=python> >>> float.fromhex('0x3.a7d4') ; float.fromhex('0x3a7d4p-16') ; 0x3A7D4 * (16**(-4)) 3.65557861328125 3.65557861328125 3.65557861328125 >>> </syntaxhighlight> ====point float with exponent==== Consider <code>f1 = float.fromhex('0x3.a7p10')</code>. f1 = <math>(3 + \frac{0xA}{16} + \frac{0x7}{16^2} ) * (2^{10})</math> To simplify the conversion put the hex string in the format of exponent float without decimal point: <syntaxhighlight lang=python> >>> float.fromhex('0x3.a7p10') ; float.fromhex('0x3a7p2') ; 0x3A7 * (2 ** 2) 3740.0 3740.0 3740 >>> </syntaxhighlight> ====1/3==== Consider <code>f1 = float.fromhex('0x0.55555555555555555555')</code> f1 = <math>(0 + \frac{5}{16} + \frac{5}{16^2} + \frac{5}{16^3} + ... + \frac{5}{16^{20}})</math> To simplify calculation of f1: f1 = <math>0x \underbrace{55555555555555555555}_\text{20 hex digits} (16^{-20}) = 0x55555555555555555555(2^{-80})</math> <syntaxhighlight lang=python> >>> fives = '0x' + '5'*20 ; fives '0x55555555555555555555' >>> >>> v1 = '0x0.'+fives[2:] ; v1 '0x0.55555555555555555555' # Point float. >>> >>> v2 = fives + 'p-80' ; v2 '0x55555555555555555555p-80' # Exponent float without point. >>> >>> v3 = fives[:-18] + '.' + fives[-18:] + 'p-8' ; v3 '0x55.555555555555555555p-8' # Point float with exponent. >>> >>> float.fromhex(v1) ; float.fromhex(v2) ; float.fromhex(v3) ; eval(fives)*(2**(-80)) 0.3333333333333333 0.3333333333333333 0.3333333333333333 0.3333333333333333 >>> >>> v4 = '0x' + hex( eval(fives) << 3 )[2:].upper() + 'p-83' ; v4 '0x2AAAAAAAAAAAAAAAAAAA8p-83' # Exponent float with significand shifted left 3 bits. >>> float.fromhex(v4) 0.3333333333333333 >>> </syntaxhighlight> Exact value of hex string representing <math>\frac{1}{3}</math> <code>= '0x55555555555555555555p-80' =</code> <math>\frac{0x55555555555555555555}{2^{80}}.</math> <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec = 100 >>> >>> d1 = Decimal( eval(fives) ) / Decimal(2**80) ; d1 Decimal('0.33333333333333333333333305760646248232410837619710264334571547806262969970703125') >>> float(d1) 0.3333333333333333 >>> len(str(d1)) 82 # Well within precision of 100. >>> </syntaxhighlight> ====More room for error with greater precision==== Consider the hex representation of float <code>0.03</code>. <syntaxhighlight lang=python> >>> (0.03).hex() '0x1.eb851eb851eb8p-6' >>> </syntaxhighlight> See what happens when there is an error of only 1 in the rightmost hex digit: <syntaxhighlight lang=python> >>> float.fromhex('0x1.eb851eb851eb8p-6') 0.03 >>> float.fromhex('0x1.eb851eb851eb7p-6') 0.029999999999999995 >>> float.fromhex('0x1.eb851eb851eb9p-6') 0.030000000000000002 >>> </syntaxhighlight> With limited precision calculations have to be perfect because there is no room for error. See what happens when there is greater precision: <syntaxhighlight lang=python> >>> float.fromhex('0x1eb851eb851eb77fffffp-82') 0.029999999999999995 >>> float.fromhex('0x1eb851eb851eb7800000p-82') 0.03 >>> float.fromhex('0x1eb851eb851eb8800000p-82') 0.03 >>> float.fromhex('0x1eb851eb851eb8800001p-82') 0.030000000000000002 >>> >>> eval('0x1eb851eb851eb8800000') - eval('0x1eb851eb851eb77fffff') 16,777,217 # A range of more than 16,000,000 values that all convert to 0.03. >>> </syntaxhighlight> Less than perfect floating point calculations can be tolerated when there is greater precision in the underlying calculations. If floating point software with greater precision were to be used, reset the underlying hex value when it's obvious that it should reflect the correct value of the displayed float. <syntaxhighlight lang=python> >>> h1 >>> '0x1eb851eb851eb7812345p-82' >>> float.fromhex(h1) 0.03 >>> h1 = '0x1eb851eb851eb851eb85p-82' # Most accurate hex representation of float 0.03 with this precision. >>> float.fromhex(h1) 0.03 >>> </syntaxhighlight> {{RoundBoxBottom}} ===to hex=== {{RoundBoxTop|theme=3}} Instance method <code>float.hex()</code> returns a representation of a floating-point number as a hexadecimal string. <syntaxhighlight lang=python> >>> (24.567).hex() '0x1.89126e978d4fep+4' # 13 places of hex decimals. >>> >>> float.fromhex('0x189126e978d4fep-48') 24.567 >>> </syntaxhighlight> The significand in standard form: <math>0x1 \underbrace{89126e978d4fe}_\text{13 hex digits}</math> Number of bits in significand = <code>1 + 13*4 = 53.</code> Recall that <code>sys.float_info.mant_dig = 53.</code> ====In standard form==== Conversion to hex string with 13 places of decimals as above: <math>\frac{24567}{1000} = \frac{x}{16^{13}};</math> <math>x = \frac{24567(16^{13})}{1000}</math> <syntaxhighlight lang=python> >>> x,r = divmod( 24567*(16**13), 1000 ) ; x; r 110639932045610975 232 >>> h1 = '0x' + hex(x)[2:].upper() ; h1 '0x189126E978D4FDF' >>> v1 = h1 + 'p-52' ; v1 '0x189126E978D4FDFp-52' >>> float.fromhex(v1) 24.567 >>> x.bit_length() 57 >>> </syntaxhighlight> Truncate and round <code>x</code> so that the result fits in 53 bits: <syntaxhighlight lang=python> >>> x1 = (x >> 4) + ((x & 0xF) >= 8) ; x1 ; hex(x1) 6914995752850686 '0x189126e978d4fe' >>> x1.bit_length() 53 >>> h1a = '0x' + hex(x1)[2:].upper() ; h1a '0x189126E978D4FE' >>> >>> v1a = h1a + 'p-48' ; v1a '0x189126E978D4FEp-48' # Exponent float. >>> v1b = h1a[:-12] + '.' + h1a[-12:] ; v1b '0x18.9126E978D4FE' # Point float >>> v1c = h1a[:-13] + '.' + h1a[-13:] + 'p+4' ; v1c '0x1.89126E978D4FEp+4' # Standard format, point float with exponent. >>> >>> float.fromhex(v1a) ; float.fromhex(v1b) ; float.fromhex(v1c) 24.567 24.567 24.567 >>> v1c.lower() == (24.567).hex() True >>> </syntaxhighlight> ====float.as_integer_ratio()==== Instance method <code>float.as_integer_ratio()</code> returns a pair of integers whose ratio is exactly equal to the hex representation of the original float and with a positive denominator. <syntaxhighlight lang=python> >>> a,b = (1.13 - 1.1).as_integer_ratio(); a; b; a/b 67553994410557 2251799813685248 0.029999999999999805 >>> </syntaxhighlight> <math>\frac{a}{b} = \frac{67553994410557}{2251799813685248} = \frac{0x3d70a3d70a3d}{2^{51}}</math> = <code>'0x3d70a3d70a3dp-51'.</code> <syntaxhighlight lang=python> >>> float.fromhex('0x3d70a3d70a3dp-51') 0.029999999999999805 >>> </syntaxhighlight> ====Conversion with more precision than standard form==== To convert <code>24.567</code> to hex with greater precision than standard form: Get the power of 2 in standard form: <syntaxhighlight lang=python> >>> a,b = (24.567).as_integer_ratio() >>> power_of_2 = len(bin(b))-3 >>> b == 2**power_of_2 True >>> </syntaxhighlight> Decide what precision you want. For example, with 4 more hex digits. <syntaxhighlight lang=python> >>> power_of_2 += 16 >>> power_of_2 63 >>> </syntaxhighlight> Get the value of float <code>24.567</code> as the exact ratio of two integers: <syntaxhighlight lang=python> >>> a1,b1 = Decimal(str(24.567)).as_integer_ratio();a1;b1 24567 1000 >>> </syntaxhighlight> <math>\frac{24567}{1000} = \frac{x}{2^{63}};\ x = \frac{24567(2^{63})}{1000}</math> <syntaxhighlight lang=python> >>> x,r = divmod( 24567*(2**63),1000 );x;r 226590580829411277275 136 >>> h1 = hex(x).upper().replace('X','x') + 'p-63' ; h1 '0xC489374BC6A7EF9DBp-63' >>> float.fromhex(h1) 24.567 >>> </syntaxhighlight> Exact value of <code>24.567:</code> <syntaxhighlight lang=python> >>> d1 = Decimal(24.567);d1;float(d1) Decimal('24.5670_0000_0000_0001_7053025658242404460906982421875') # 17 significant digits. 24.567 >>> </syntaxhighlight> Exact value of <code>24.567</code> with greater precision (h1): <syntaxhighlight lang=python> >>> d2 = Decimal( eval(h1[:-4]) ) / Decimal(2**63);d2;float(d2) Decimal('24.5669_9999_9999_9999_9998_5254850454197139697498641908168792724609375') # 21 significant digits. 24.567 >>> </syntaxhighlight> Compare the differences: <syntaxhighlight lang=python> >>> diff1 = Decimal('24.567') - d1 >>> diff2 = Decimal('24.567') - d2 >>> diff1;diff2 Decimal('-1.7053025658242404460906982421875E-16') Decimal('1.4745149545802860302501358091831207275390625E-20') >>> </syntaxhighlight> ====Exact conversion==== The only floating point numbers that can be converted exactly to hex are those that, when expressed as a fraction, have a divisor that is an integer power of 2. <syntaxhighlight lang=python> >>> (1+71/(2**67)).hex() '0x1.0000000000000p+0' >>> </syntaxhighlight> To convert <code>1+71/(2**67)</code> to hex exactly: <math>1+\frac{71}{2^{67}}</math> <math> = 1+\frac{142}{2^{68}}</math> <math> = 1+\frac{0x8E}{16^{17}}</math> <math> = 0x1\_\underbrace{0000\_0000\_0000\_0008\_E}_\text{17 hex digits} (16^{-17})</math> <math> = 0x1.0000000000000008E</math> <math> = 0x10000000000000008E(2^{-68})</math> <syntaxhighlight lang=python> >>> h1 = '0x1' + '0'*15 + '8E' ; h1 '0x10000000000000008E' >>> v1 = h1+'p-68' ; v1 '0x10000000000000008Ep-68' # exact hex value of 1 + 71/(2**67) >>> float.fromhex(v1) 1.0 # lack of precision. >>> >>> getcontext().prec 150 >>> d1 = Decimal(1) + Decimal(71)/Decimal(2**67) ; d1 Decimal('1.0000000000000000004811147140404425925908071803860366344451904296875') # exact decimal value of 1 + 71/(2**67) >>> >>> len(str(d1)) 69 >>> d2 = Decimal(eval(h1)) / Decimal(2**68) ; d2 Decimal('1.0000000000000000004811147140404425925908071803860366344451904296875') # exact decimal value of '0x10000000000000008Ep-68' >>> d1 == d2 True >>> >>> float(d1) 1.0 >>> </syntaxhighlight> {{RoundBoxBottom}} ===Floating point calculation of <code>1.13 - 1.1</code>=== {{RoundBoxTop|theme=3}} <syntaxhighlight lang=python> >>> (1.1).hex() '0x1.199999999999ap+0' >>> v1 = '0x1199999999999Ap-52' ; float.fromhex(v1) 1.1 >>> >>> (1.13).hex() '0x1.2147ae147ae14p+0' >>> v2 = '0x12147AE147AE14p-52' ; float.fromhex(v2) 1.13 >>> </syntaxhighlight> Difference <code>= 1.13 - 1.1 = v2 - v1 = '0x12147AE147AE14p-52' - '0x1199999999999Ap-52'</code> <code>= (0x12147AE147AE14 - 0x1199999999999A)</code><math>2^{-52}</math> <code>= 0x7AE147AE147A</code><math>(2^{-52})</math> <code>= '0x7AE147AE147Ap-52'</code> <syntaxhighlight lang=python> >>> float.fromhex('0x7AE147AE147Ap-52') 0.029999999999999805 >>> 1.13-1.1 0.029999999999999805 >>> </syntaxhighlight> Exact value of v1: <syntaxhighlight lang=python> >>> d1 = Decimal(eval(v1[:-4])) / Decimal(2**52) ; d1 ; d1 == Decimal(1.1) Decimal('1.100000000000000088817841970012523233890533447265625') # > 1.1 >>> True >>> </syntaxhighlight> Exact value of v2: <syntaxhighlight lang=python> >>> d2 = Decimal(eval(v2[:-4])) / Decimal(2**52) ; d2 ; d2 == Decimal(1.13) Decimal('1.12999999999999989341858963598497211933135986328125') # < 1.13 >>> True >>> </syntaxhighlight> Exact value of difference: <syntaxhighlight lang=python> >>> d1a = d2-d1 ; d1a Decimal('0.029999999999999804600747665972448885440826416015625') >>> >>> d1a == Decimal(1.13 - 1.1) >>> True >>> float(d1a) 0.029999999999999805 >>> </syntaxhighlight> ====Why the error appears to be so great==== <syntaxhighlight lang=python> >>> error2 = d2-Decimal('1.13'); error2 Decimal('-1.0658141036401502788066864013671875E-16') # Negative number. >>> >>> error1 = d1-Decimal('1.1'); error1 Decimal('8.8817841970012523233890533447265625E-17') # Positive number. >>> >>> total_error = error2-error1 ; total_error Decimal('-1.95399252334027551114559173583984375E-16') # Relatively large negative number. >>> >>> total_error + ( Decimal('1.13')-Decimal('1.1') - Decimal(1.13-1.1) ) Decimal('0E-51') >>> </syntaxhighlight> ====An observation==== While the value <code>0.03</code> does not contain a repeating decimal, it seems that there is a repeating "decimal" in the hex representation. Repeat the sequence in hex and see what happens: <syntaxhighlight lang=python> >>> diff1 = '0x7AE14_7AE14_7AE14_7AE14_7AE14p-104' >>> float.fromhex( diff1.replace('_', '') ) 0.03 >>> </syntaxhighlight> Exact decimal value of <code>diff1</code>: <syntaxhighlight lang=python> >>> diff2 = Decimal(eval(diff1[:-5])) / Decimal(2**104) ; diff2 Decimal('0.029999999999999999999999999999976334172843369645837648143041516413109803806946729309856891632080078125') >>> float(diff2) 0.03 >>> </syntaxhighlight> Should the point in the hex representation be called a "heximal" point? ====User-written floating point software for an accurate result==== <syntaxhighlight lang=python> >>> (1.13).hex() '0x1.2_147ae_147ae_14_p+0' # 13 hexadecimal digits after the hexadecimal point. >>> (1.1).hex() '0x1.1_99999_99999_9a_p+0' # 13 hexadecimal digits after the hexadecimal point. >>> </syntaxhighlight> By inspection produce hex values for <code>1.13</code> and <code>1.1</code> accurate to 14 hexadecimal places after the hexadecimal point. <syntaxhighlight lang=python> >>> v1 = '0x12_147ae_147ae_148_p-56' # '0x1.2_147ae_147ae_147ae_147ae_147ae_p+0' accurate to 14 hexadecimal digits after the hexadecimal point. >>> float.fromhex(v1.replace('_','')) 1.13 >>> >>> v2 = '0x1_19999_99999_999a_p-56' # Accurate to 14 hexadecimal digits after the hexadecimal point. >>> float.fromhex(v2.replace('_','')) 1.1 >>> </syntaxhighlight> Slightly more precision in the underlying calculations produces an accurate difference: <syntaxhighlight lang=python> >>> diff = hex(eval(v1[:-5]) - eval(v2[:-5])) + 'p-56' ; diff '0x7ae147ae147aep-56' >>> float.fromhex(diff) 0.03 >>> </syntaxhighlight> Exact value of <code>diff:</code> <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext().prec = 100 >>> >>> d1 = Decimal( eval(diff[:-4]) ) / Decimal(2**56) ; d1 Decimal('0.0299999999999999988897769753748434595763683319091796875') >>> float(d1) 0.03 >>> >>> getcontext().prec = 15 # Maximum precision of floats. >>> d1 += 0 ; d1 Decimal('0.0300000000000000') # Accurate to 15 digits of precision. >>> float(d1) 0.03 >>> </syntaxhighlight> Summary: <syntaxhighlight lang=python> >>> import sys >>> sys.float_info.mant_dig 53 >>> sys.float_info.mant_dig = 57 Traceback (most recent call last): File "<stdin>", line 1, in <module> AttributeError: readonly attribute >>> </syntaxhighlight> This section simulates the floating-point calculation of <math>1.13 - 1.1</math> if the value of attribute <code>sys.float_info.mant_dig</code> could be set to <math>57</math> by user. For examples of professionally written code that temporarily increases precision for underlying calculations and then restores precision to display result, see [https://docs.python.org/3/library/decimal.html?highlight=recipes#recipes recipes.] {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} =Miscellaneous Topics= {{RoundBoxTop|theme=3}} ==Plus zero and minus zero== {{RoundBoxTop|theme=2}} The concept of plus and minus zero does not apply to the integers: <syntaxhighlight lang="Python"> >>> +0 ; -0 0 0 >>> </syntaxhighlight> Floats retain the distinction: <syntaxhighlight lang="Python"> >>> +0. ; -0. ; +0. == -0. == 0 0.0 -0.0 True >>> </syntaxhighlight> As do complex numbers: <syntaxhighlight lang="Python"> >>> complex(-0., -0.) (-0-0j) >>> complex(-0., -0.).real -0.0 >>> complex(-0., -0.).imag -0.0 >>> </syntaxhighlight> ===Examples of plus and minus zero=== <syntaxhighlight lang="Python"> >>> '{0:0.2f}'.format(.0000) '0.00' >>> '{0:0.2f}'.format(.0003) '0.00' >>> '{0:0.2f}'.format(-.0000) '-0.00' >>> '{0:0.2f}'.format(-.0003) '-0.00' >>> </syntaxhighlight> A small non-zero positive number was displayed as <code>'0.00'</code>; a small non-zero negative number was displayed as <code>'-0.00'</code>. According to values under [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Cube_roots_of_1_simplified "Cube roots of 1 simplified,"] one of the cube roots of unity is <math>r_3 = \frac{-1 - 1j*\sqrt{3}}{2}.</math> We expect that <math>r_3^3</math> should equal <math>1.</math> However: <syntaxhighlight lang="Python"> >>> r3 = ( -1 - 1j * (3**0.5)) / 2 ; v3 = r3**3 ; v3 (0.9999999999999998-1.1102230246251565e-16j) >>> </syntaxhighlight> The best accuracy which we can expect from floats is 15 significant digits: <syntaxhighlight lang="Python"> >>> '{0:0.15f}'.format( v3.real ) '1.000000000000000' >>> '{0:0.15f}'.format( v3.imag ) '-0.000000000000000' >>> </syntaxhighlight> The respective values <code>'1.000000000000000', '-0.000000000000000'</code> are the most accurate that can be displayed with 15 places of decimals. <code>v3.imag,</code> a small non-zero negative number was displayed as <code>'-0.000000000000000'</code>. <syntaxhighlight lang="Python"> >>> float( '-0.000000000000000' ) -0.0 >>> </syntaxhighlight> The conversion from string to float preserves the distinction of minus zero, indicating that the original value was, probably, a small, non-zero, negative number. {{RoundBoxBottom}} ==Precision and formatted decimals== {{RoundBoxTop|theme=2}} Within this section the expression "decimal precision" means precision as implemented by Python's decimal module. Precision means the number of digits used to display a value beginning with and containing the first non-zero digit. Some examples using decimal precision: <syntaxhighlight lang="Python"> >>> from decimal import * >>> getcontext().prec = 4 >>> >>> Decimal('0.0034567') Decimal('0.0034567') # Precision not enforced here. >>> Decimal('0.0034567') + 0 Decimal('0.003457') # '+ 0' forces result to conform to precision of 4. >>> Decimal('0.003456432') + 0 Decimal('0.003456') >>> Decimal('3456432') + 0 Decimal('3.456E+6') >>> Decimal('3456789') + 0 Decimal('3.457E+6') >>> >>> Decimal('0.00300055') + 0 Decimal('0.003001') >>> Decimal('0.00300033') + 0 Decimal('0.003000') # Trailing Zeroes are retained to conform to precision of 4. >>> </syntaxhighlight> Note how the following values are rounded. More about rounding in the next section. <syntaxhighlight lang="Python"> >>> from decimal import * >>> getcontext().prec = 4 >>> >>> Decimal('3456500') + 0 Decimal('3.456E+6') # Rounded down. >>> Decimal('3457500') + 0 Decimal('3.458E+6') # Rounded up. >>> </syntaxhighlight> Python's string method <code>.format</code> can be used to display a value accurate to a given number of decimal positions. <syntaxhighlight lang="Python"> >>> '{0:.4f}'.format(0.003456) '0.0035' # Accurate to four places of decimals. >>> '{0:.4f}'.format(0.003446) '0.0034' # Accurate to four places of decimals. >>> </syntaxhighlight> Default rounding provided by python's string method <code>.format</code> is same as that for decimal precision: <syntaxhighlight lang="Python"> >>> >>> '{0:.4f}'.format(0.00345) '0.0034' # Rounded down. >>> '{0:.4f}'.format(0.00355) '0.0036' # Rounded up. >>> </syntaxhighlight> {{RoundBoxBottom}} ==Rounding of close but inexact values== {{RoundBoxTop|theme=2}} Even elementary calculations lead to increasing complexity in the practical execution of a task involving numbers. It is fairly easy to imagine one fifth of one inch shown mathematically as <math>\frac{1}{5}</math> inch. What if you had to cut from a piece of steel rod a smaller piece with an exact length of <math>\frac{1}{5}</math> inch? Most [https://en.wikipedia.org/wiki/Tape_measure#Types common measuring instruments] have lengths expressed in inches and sixteenths of an inch. Then <math>\frac{1}{5}</math> inch becomes <math>\frac{3.2}{16}</math> inch. You use a [https://en.wikipedia.org/wiki/Micrometer#Customary/Imperial_system micrometer measuring instrument] accurate to <math>\frac{1}{1000}</math> inch and <math>\frac{200}{1000}</math> inch is <math>\frac{1}{5}</math> inch exactly. What if you had to produce a piece of steel rod with length <math>\frac{1}{7}</math> feet exactly? <math>\frac{1}{7}</math> feet = <math>\frac{12}{7}</math> inches = <math>1.714285714285</math> inches = <math>1\frac{11.428571428571}{16}</math> inches. Both the measuring tape and micrometer seem inadequate for the task. You devise a system dependent on similar triangles and parallel lines. Success. The value <math>\frac{1}{7}</math> can be produced geometrically. What if you had to produce a square with an exact area of <math>2</math> square inches? The side of the square would be <math>\sqrt{2}</math> inches exactly, but how do you measure <math>\sqrt{2}</math> inches exactly? In practical terms your task becomes feasible if some tolerance in the area of the finished product is allowed, for example <math>2 \pm 0.0002</math> square inches. Then a "square" with adjacent sides of 1.4142 and 1.4143 inches has an area within the specified tolerance. ===DRIP for example=== Even simple calculations based on exact decimals quickly lead to impractical numbers. Suppose you have a DRIP ([https://en.wikipedia.org/wiki/Dividend_reinvestment_plan Dividend ReInvestment Plan]) with any of the big well-known corporations. Most DRIPs permit you to purchase fractions of a share of stock. Shares of an attractive stock are currently trading for <math>\$38</math> and you invest <math>\$100</math>, buying <math>\frac{100}{38}</math> shares of stock. On your statement you don't see a credit of <math>2\frac{24}{38}</math> shares of stock. The custodian of the plan may show your holding accurate to four places of decimals: <math>2.6315</math> shares. The fraction <math>\frac{24}{38}</math> is actually <math>0.63157894736........</math> but your credit is <math>2.6315</math> called 'rounding down.' The corporation then issues a dividend of <math>\$0.37</math> per share when the stock is trading for <math>\$37.26</math> per share and you reinvest the dividend. If the custodian reinvests the dividend for you at a <math>5\%</math> discount to market price, your credit is <math>\frac{0.37 * 2.6315}{37.26 * 0.95} = 0.02750670960.....</math> shares, shown on your statement as <math>0.0275</math> shares giving you a total holding of <math>2.6315 + 0.0275 = 2.659</math> shares probably shown on your statement as <math>2.6590</math> with a current market value of <math>\$2.659 * 37.26 = \$99.07434</math> shown on your statement as <math>\$99.07</math>. The result of your mathematical calculations will probably be a close approximation of the exact value after allowing for tolerable errors based on precision and rounding of intermediate results. ===Default rounding=== When you import python's decimal module, values are initialized as the 'default' values. <syntaxhighlight lang=python> >>> from decimal import * >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> setcontext(DefaultContext) >>> getcontext() Context(prec=28, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) # Same as above. >>> </syntaxhighlight> The default rounding method is called [https://docs.python.org/3/library/decimal.html#decimal.ROUND_HALF_EVEN <code>ROUND_HALF_EVEN</code>]. This means that, if your result is exactly half-way between two limits, the result is rounded to the nearest even number. For simplicity set precision to 4: <syntaxhighlight lang=python> >>> getcontext().prec = 4 >>> getcontext() Context(prec=4, rounding=ROUND_HALF_EVEN, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> >>> Decimal('0.012344') + 0 Decimal('0.01234') >>> Decimal('0.012345') + 0 Decimal('0.01234') # Rounded down to nearest even number. >>> Decimal('0.045674') + 0 Decimal('0.04567') >>> Decimal('0.045675') + 0 Decimal('0.04568') # Rounded up to nearest even number. >>> </syntaxhighlight> Default rounding provided by python's string method .format is same as that for decimal precision: <syntaxhighlight lang=python> >>> >>> '{0:.4f}'.format(0.00345) '0.0034' # Rounded down. >>> '{0:.4f}'.format(0.00355) '0.0036' # Rounded up. >>> </syntaxhighlight> A disadvantage of this method of rounding is that an examination of the result does not indicate what the original value was: <syntaxhighlight lang=python> >>> Decimal('0.045675') + 0 == Decimal('0.045685') + 0 True >>> </syntaxhighlight> ===Other rounding modes=== ====ROUND_HALF_UP==== Rounding mode [https://docs.python.org/3/library/decimal.html#decimal.ROUND_HALF_UP ROUND_HALF_UP] is illustrated as follows: <syntaxhighlight lang=python> >>> getcontext().rounding=ROUND_HALF_UP >>> getcontext() Context(prec=4, rounding=ROUND_HALF_UP, Emin=-999999, Emax=999999, capitals=1, clamp=0, flags=[], traps=[InvalidOperation, DivisionByZero, Overflow]) >>> >>> Decimal('0.012345') + 0 Decimal('0.01235') >>> Decimal('0.012355') + 0 Decimal('0.01236') >>> Decimal('0.012365') + 0 Decimal('0.01237') >>> Decimal('0.012375') + 0 Decimal('0.01238') </syntaxhighlight> Same logic for negative numbers: <syntaxhighlight lang=python> >>> Decimal('-0.012345') + 0 Decimal('-0.01235') >>> Decimal('-0.012355') + 0 Decimal('-0.01236') >>> Decimal('-0.012365') + 0 Decimal('-0.01237') >>> Decimal('-0.012375') + 0 Decimal('-0.01238') </syntaxhighlight> ====ROUND_DOWN==== The numbers in the example under DRIP above are derived using python's [https://docs.python.org/3/library/decimal.html#decimal.Decimal.quantize <code>.quantize()</code>] method and rounding set to [https://docs.python.org/3/library/decimal.html#decimal.ROUND_DOWN ROUND_DOWN]. <syntaxhighlight lang=python> setcontext(DefaultContext) number_of_initial_shares = 100/38 print ('number_of_initial_shares =', number_of_initial_shares) number_of_initial_shares = Decimal(number_of_initial_shares).quantize(Decimal('.0001'), rounding=ROUND_DOWN) print ( '''After rounding down number_of_initial_shares =''', number_of_initial_shares ) shares_added = 0.37*float(number_of_initial_shares) / (37.26*0.95) print (''' shares_added =''', shares_added) shares_added = Decimal(shares_added).quantize(Decimal('.0001'), rounding=ROUND_DOWN) print ( '''After rounding down shares_added =''', shares_added ) total_shares = shares_added + number_of_initial_shares value = total_shares * Decimal('37.26') print (''' value =''', value) value = value.quantize(Decimal('.01'), rounding=ROUND_DOWN) print ( '''After rounding down value =''', '$'+str(value) ) </syntaxhighlight> <syntaxhighlight lang="Python"> number_of_initial_shares = 2.6315789473684212 After rounding down number_of_initial_shares = 2.6315 shares_added = 0.02750670960815888 After rounding down shares_added = 0.0275 value = 99.074340 After rounding down value = $99.07 </syntaxhighlight> When using method <code>.quantize(....)</code>, ensure that <code>getcontext().prec</code> is adequate: <syntaxhighlight lang=python> >>> getcontext().prec = 6 >>> Decimal('0.0000123456').quantize(Decimal('1e-6')) Decimal('0.000012') >>> Decimal('123.0000123456').quantize(Decimal('1e-6')) Traceback (most recent call last): File "<stdin>", line 1, in <module> decimal.InvalidOperation: [<class 'decimal.InvalidOperation'>] >>> getcontext().prec = 9 >>> Decimal('123.0000123456').quantize(Decimal('1e-6')) Decimal('123.000012') # Desired result has precision of 9. >>> </syntaxhighlight> {{RoundBoxBottom}} {{RoundBoxBottom}} =Assignments= {{RoundBoxTop|theme=4}} [[File:Crystal_Clear_app_kedit.svg|right|100px]] * Experiment with the python interpreter using integers, floats, Booleans, and complex numbers, noting errors, for example: <syntaxhighlight lang=python> >>> + 44 ; eval(' - 33 ') ; eval(' - 0003.e-002 ') ; eval(' + 0003.00000E-002 ') ; eval(' + 0003.12E0073 ') >>> + 4 + 1j*3 ; complex(2,-3) ; complex("2+3j") ; eval("2+3J") ; complex('-3',7j) >>> bool(6) ; bool(0) ; bool('0') ; '123'+0 ; bool('123') + 1 ; 1+3 == 4 ; 2**2 == -3 </syntaxhighlight> * Think critically about integers and floats. When should you use integers? When should you use floats? * A [[Wikipedia:Loss of significance|loss of significance]] for a float value should be expected when working with long or insignificant numbers. When would this become a problem? * Under [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Using_formatted_string "Using formatted string"] above the test for correct summation is: <syntaxhighlight lang=python> if sum != count / 10_000_000_000 : </syntaxhighlight> This could be written as: <syntaxhighlight lang=python> if sum != count * increment : </syntaxhighlight> However: <syntaxhighlight lang=python> >>> 5*(1e-10) ; 6*(1e-10) ; 7*(1e-10) 5e-10 6e-10 7.000000000000001e-10 >>> >>> 7 / (1e10) 7e-10 >>> </syntaxhighlight> How would you write the line <code>if sum != count * increment :</code> to ensure an accurate test? * Using techniques similar to those contained in section [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Cube_roots_of_1_simplified "Cube roots of 1 simplified"] calculate [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1977300#Fifth_roots_of_unity all five] of the fifth roots of unity. * Using the [https://en.wikiversity.org/wiki/Python_Concepts/Numbers#Proof_2 "Proof"] under "Multiplication of complex numbers" [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1977300#Division_of_complex_numbers_in_polar_format show that]: <math>\frac{\cos A + 1j*\sin A}{\cos B + 1j*\sin B} = \cos(A-B) + 1j* \sin (A-B)</math> * One of the cube roots of unity, <math>r_2 = \frac{-1+1j*\sqrt{3}}{2}.</math> For greater precision than is available with floating point arithmetic, [https://en.wikiversity.org/w/index.php?title=Python_Concepts/Numbers&oldid=1979009#Python's_decimal_module_for_greater_precision use Python's decimal module] to calculate <math>r_2^3.</math> {{RoundBoxBottom}} =Further Reading or Review= {{RoundBoxTop|theme=2}} {{testing}} * [[../To Get You Started/ | Previous Lesson: To Get You Started]] * [https://en.wikiversity.org/wiki/Python_Concepts/Numbers This Lesson:Numbers] * [[../Strings/ | Next Lesson: Strings]] * [[../ | Course Home Page]] {{RoundBoxBottom}} =References= {{reflist}} Python's built-in functions: [https://docs.python.org/3/library/functions.html#abs "abs()"], [https://docs.python.org/3/library/functions.html#bin "bin()"], [https://docs.python.org/3/library/functions.html#bool "bool()"], [https://docs.python.org/3/library/functions.html#complex "complex()"], [https://docs.python.org/3/library/functions.html#divmod "divmod()"], [https://docs.python.org/3.4/library/functions.html?highlight=eval#eval "eval(expression, ....)"], [https://docs.python.org/3/library/functions.html#float "float()"], [https://docs.python.org/3/library/functions.html#hex "hex()"], [https://docs.python.org/3/library/functions.html#int "int()"], [https://docs.python.org/3/library/functions.html#oct "oct()"], [https://docs.python.org/3/library/functions.html#pow "pow()"], [https://docs.python.org/3/library/functions.html#round "round()"], [https://docs.python.org/3.4/library/sys.html?highlight=sys.exc#sys.float_info "sys.float_info"], [https://docs.python.org/3.4/library/sys.html?highlight=sys.exc#sys.int_info "sys.int_info"] Python's documentation: [https://docs.python.org/3/tutorial/introduction.html#numbers "3.1.1. Numbers"], [https://docs.python.org/3/library/stdtypes.html#typesnumeric "Numeric Types"], [https://docs.python.org/3/reference/lexical_analysis.html#integer-literals "Integer literals"], [https://docs.python.org/3/reference/lexical_analysis.html#floating-point-literals "Floating point literals"], [https://docs.python.org/3/reference/lexical_analysis.html#imaginary-literals "Imaginary literals"], [https://docs.python.org/3/reference/expressions.html#operator-precedence "Operator precedence"], [https://docs.python.org/3/faq/design.html?highlight=goto#why-are-floating-point-calculations-so-inaccurate "Why are floating-point calculations so inaccurate?"], [https://docs.python.org/3.4/tutorial/floatingpoint.html#floating-point-arithmetic-issues-and-limitations "15. Floating Point Arithmetic: Issues and Limitations"], [https://docs.python.org/3.4/library/decimal.html?highlight=decimal#module-decimal "9.4. decimal — Decimal fixed point and floating point arithmetic"], [https://docs.python.org/3/library/stdtypes.html#additional-methods-on-integer-types "4.4.2. Additional Methods on Integer Types"], [https://docs.python.org/3/library/stdtypes.html#additional-methods-on-float "4.4.3. Additional Methods on Float"] [https://docs.python.org/3/library/cmath.html?highlight=isclose#cmath.isclose "cmath.isclose(a, b, ....)"] [[Category:Python|{{SUBPAGENAME}}]] g08qye2bfuvisl7ugcaci2jp491yg9i 102 206220 2408180 2408137 2022-07-20T13:49:25Z Dave Braunschweig 426084 Reverted edits by [[Special:Contributions/41.105.178.176|41.105.178.176]] ([[User_talk:41.105.178.176|talk]]) to last version by [[User:Dave Braunschweig|Dave Braunschweig]] using [[Wikiversity:Rollback|rollback]] wikitext text/x-wiki [[File:Nuvola apps korganizer.png|right|64px]] [[Wikiversity:Be bold|Be bold!]] Help us improve Wikiversity by participating and contributing your expertise. Post any questions you have in the [[Wikiversity:Colloquium]]. {{clear}} qbtagqzxuokkpy4lkm38ef1m8f5jx2m 0 207111 2408187 2404947 2022-07-20T16:09:47Z Maddiegray11 2936309 /* Recommended diagnostic interviews for schizophrenia */ Made the table un-sortable wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== For background information on what assessment portfolios are, click the link in the heading above. Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Schizophrenia (disorder portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic Criteria for Schizophrenia === {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *<big>'''Schizophrenia'''</big> **Schizophrenia is characterized by disturbances in multiple mental modalities, including thinking (e.g., delusions, disorganization in the form of thought), perception (e.g., hallucinations), self-experience (e.g., the experience that one's feelings, impulses, thoughts, or behaviour are under the control of an external force), cognition (e.g., impaired attention, verbal memory, and social cognition), volition (e.g., loss of motivation), affect (e.g., blunted emotional expression), and behaviour (e.g.,behaviour that appears bizarre or purposeless, unpredictable or inappropriate emotional responses that interfere with the organization of behaviour). Psychomotor disturbances, including catatonia, may be present. Persistent delusions, persistent hallucinations, thought disorder, and experiences of influence, passivity, or control are considered core symptoms. Symptoms must have persisted for at least one month in order for a diagnosis of schizophrenia to be assigned. The symptoms are not a manifestation of another health condition (e.g., a brain tumour) and are not due to the effect of a substance or medication on the central nervous system (e.g., corticosteroids), including withdrawal (e.g., alcohol withdrawal). *<big>'''Schizophrenia, First Episode'''</big> **Schizophrenia, first episode should be used to identify individuals experiencing symptoms that meet the diagnostic requirements for Schizophrenia (including duration) but who have never before experienced an episode during which diagnostic requirements for Schizophrenia were met. ***Note: The ICD-11 lists 3 additional subcategories of schizophrenia, first episode. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f625636921 here]. *<big>'''Schizophrenia, Multiple Episodes'''</big> **Schizophrenia, multiple episode should be used to identify individuals experiencing symptoms that meet the diagnostic requirements for Schizophrenia (including duration) and who have also previously experienced episodes during which diagnostic requirements were met, with substantial remission of symptoms between episodes. Some attenuated symptoms may remain during periods of remission, and remissions may have occurred in response to medication or other treatment. ***Note: The ICD-11 lists 3 additional subcategories of schizophrenia, multiple episodes. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1150025154 here]. '''Changes in DSM-5''' The diagnostic criteria for schizophrenia spectrum and other psychotic disorders changed slightly from DSM-IV to DSM-5. A summary is available [https://en.wikipedia.org/wiki/DSM-5#Section_II:_diagnostic_criteria_and_codes here]. {{blockquotebottom}} === Base rates of schizophrenia in different populations and clinical settings === {| class="wikitable sortable" |- ! Setting !! Base Rate !! Demography !! Diagnostic Method |- | Non-institutionalized civilians<ref name="KesslerEtAl1994" /> || 0.5% || 48 contiguous US states || CIDI, SCID |- | Community sample<ref name="RobinsRegiers1991" /> || 1.3% || Urban settings in 5 states (MD, NC, CN, CA, MO) || DIS |- | Inmates with severe mental disorders<ref name="DumaisEtAl2010" /> || 23.5% incarcerated†, 69.7% hospitalized involuntarily† || All Federal Penitentiaries in Quebec-incarcerated and inmates currently hospitalized involuntarily || SCID |- | Patients presenting for inpatient and ambulatory services<ref name="MinskyEtAl2003" /> || *African-American (males – 19.1%, females – 11.3%) *Latino (males – 9.4%, females – 6.2%) *European-American (males – 9.9%, females – 6.1%) *(Rates are for all psychotic disorders – authors note this was “mostly schizophrenia”) || New Jersey || BASIS-32 |- | General population (community, inpatient, and outpatient)<ref>{{Cite journal|last=Saha|first=Sukanta|last2=Chant|first2=David|last3=Welham|first3=Joy|last4=McGrath|first4=John|date=May 2005|title=A systematic review of the prevalence of schizophrenia|url=https://www.ncbi.nlm.nih.gov/pubmed/15916472|journal=PLoS medicine|volume=2|issue=5|pages=e141|doi=10.1371/journal.pmed.0020141|issn=1549-1676|pmc=PMC1140952|pmid=15916472}}</ref> ||0.7% || Global – 44 countries || Clinical interview |- | General population<ref>{{Cite journal|last=Perälä|first=Jonna|last2=Suvisaari|first2=Jaana|last3=Saarni|first3=Samuli I.|last4=Kuoppasalmi|first4=Kimmo|last5=Isometsä|first5=Erkki|last6=Pirkola|first6=Sami|last7=Partonen|first7=Timo|last8=Tuulio-Henriksson|first8=Annamari|last9=Hintikka|first9=Jukka|date=January 2007|title=Lifetime prevalence of psychotic and bipolar I disorders in a general population|url=https://www.ncbi.nlm.nih.gov/pubmed/17199051|journal=Archives of General Psychiatry|volume=64|issue=1|pages=19–28|doi=10.1001/archpsyc.64.1.19|issn=0003-990X|pmid=17199051}}</ref> || 0.87% || Finland || CIDI, SCID |- | County Mental Health Service Users<ref name="FolsomEtAl2005" /> || 54% - homeless individuals || San Diego County || Chart Diagnosis |- | Inpatient service<ref>{{Cite journal|last=Brown|first=Samuel L.|date=2001-06-01|title=Variations in Utilization and Cost of Inpatient Psychiatric Services Among Adults in Maryland|url=https://ps.psychiatryonline.org/doi/abs/10.1176/appi.ps.52.6.841|journal=Psychiatric Services|volume=52|issue=6|pages=841–843|doi=10.1176/appi.ps.52.6.841|issn=1075-2730}}</ref> || *39% - non-homeless *8.4% - 65 years and up *17% - 19-64 years || Maryland || Psychiatrist Diagnosis |- | Insurance claimants in 2002<ref name="WuEtAl2006" /> || Medicaid – 1.66%, Uninsured – 1.02%, Medicare – 0.83%, Privately insured – 0.13%, Veterans (through VA) – 1.41% || USA (Note: Medicaid rate was calculated using California Medi-Cal rates as a proxy) || Physician diagnosis |} †Rates reflect schizophrenia spectrum disorders. '''Note:''' DIS = Diagnostic Interview Schedule, CIDI = Composite International Diagnostic Interview, SCID = Structured Diagnostic Interview for DSM, BASIC-32 = Behavior and Symptoms Identification Scale '''Search terms:''' [Schizophrenia] AND [prevalence OR incidence], [Schizophrenia] AND [Prevalence] AND [Outpatient OR inpatient] in PsycINFO, Medline, and PubMed ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== ===Recommended screening instruments === The following section contains a list of screening and diagnostic instruments for schizophrenia. {| class="wikitable" |+ !Screening Instrument !Format !Age Range !Administration Time !Where to Access |- |Psychiatric Diagnostic Screening Questionnaire (PDSQ)<ref>{{Cite web|url=https://www.wpspublish.com/pdsq-psychiatric-diagnostic-screening-questionnaire|title=(PDSQ™) Psychiatric Diagnostic Screening Questionnaire™ {{!}} WPS|website=www.wpspublish.com|accessdate=2018-03-08}}</ref> |Self-report, yes-or-no items |Ages 18+ |15-20 minutes | -Available from [https://www.wpspublish.com/pdsq-psychiatric-diagnostic-screening-questionnaire Western Psychological Services] |- |Structured Interview for Psychosis-Risk Syndrome (SIPS) <ref name=":0">{{Cite book|url=https://www.worldcat.org/oclc/897376853|title=The assessment of psychosis : a reference book and rating scales for research and practice|author=Waters, Flavie |author2=Stephane, Massoud|isbn=9781315885605|location=New York, NY|oclc=897376853}}</ref> |Structured interview by a clinician or experienced rater |Pre-clinical adolescents and adults |2-3 hours | -Available from PRIME clinic at Yale University, contact Dr. Barbara Walsh at 203-974-7052 -[http://www.easacommunity.org/PDF/SIPS_5-5_032514&#x5B;1&#x5D;%20correct.pdf PDF Version] |- |Bonn Scale for the Assessment of Basic Symptoms (BSABS)<ref name=":0" /> |Semi-structured interview by a clinician or experienced rater |Pre-clinical, residual, and at-risk adolescents and adults |2-3 hours | -Available from [https://www.amazon.com/BSABS-Scale-Assessment-Basic-Symptoms/dp/3832271732 Amazon] -Available from publisher [https://www.shaker.de/de/index.asp?lang=de Shaker Verlag] |- |Strengths and Difficulties Questionnaire (SDQ) <ref>{{Cite journal|last=Goodman|first=Robert|last2=Ford|first2=Tamsin|last3=Simmons|first3=Helen|last4=Gatward|first4=Rebecca|last5=Meltzer|first5=Howart|date=2000-12|title=Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders in a community sample|url=https://www.cambridge.org/core/product/identifier/S0007125000156065/type/journal_article|journal=British Journal of Psychiatry|language=en|volume=177|issue=6|pages=534–539|doi=10.1192/bjp.177.6.534|issn=0007-1250}}</ref> |Parent/teacher-report, self-report, rate items |Ages 2+ |5-25 minutes | -Available from [https://www.sdqinfo.org/py/sdqinfo/b3.py?language=Englishqz(USA) Youth In Mind] -[https://osf.io/dzk68/?view_only=681e9b648169427b845f313aafa0a169 PDF Version] |} === Likelihood ratios and AUCs of screening measures for schizophrenia === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! scope="col" style="width: 225px;" | Screening Measure (Primary Reference) ! scope="col" style="width: 100px;" | AUC ! scope="col" style="width: 100px;" | LR+ (Score) ! scope="col" style="width: 100px;" | LR- (Score) ! scope="col" style="width: 225px;"| Clinical generalizability !Where to Access |- | Psychiatric Diagnostic Screening Questionnaire – PDSQ (Zimmerman & Mattia, 2001a; Zimmerman & Sheeran, 2004)<ref name=ZimmermanMattia2001/><ref>{{Cite journal|last=Zimmerman|first=Mark|last2=Sheeran|first2=Thomas|date=2003-03|title=Screening for principal versus comorbid conditions in psychiatric outpatients with the Psychiatric Diagnostic Screening Questionnaire|url=https://pubmed.ncbi.nlm.nih.gov/12674730|journal=Psychological Assessment|volume=15|issue=1|pages=110–114|doi=10.1037/1040-3590.15.1.110|issn=1040-3590|pmid=12674730}}</ref>‡ || .92 (N = 799) || 2.7 (Subscale cutoff score = 1) || .33 (Subscale cutoff score = 1) || Low – can distinguish psychotic disorders from non-psychotic disorders but cannot distinguish schizophrenia from other psychotic disorders (ex: MDD with psychosis) |Not free |- | Structured Interview for Prodromal Syndromes – SIPS (Miller et al., 1999, 2003)<ref name=MillerEtAl1999/> <ref>{{Cite journal|last=Miller|first=Tandy J.|last2=McGlashan|first2=Thomas H.|last3=Rosen|first3=Joanna L.|last4=Cadenhead|first4=Kristen|last5=Cannon|first5=Tyrone|last6=Ventura|first6=Joseph|last7=McFarlane|first7=William|last8=Perkins|first8=Diana O.|last9=Pearlson|first9=Godfrey D.|date=2003|title=Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability|url=https://pubmed.ncbi.nlm.nih.gov/14989408|journal=Schizophrenia Bulletin|volume=29|issue=4|pages=703–715|doi=10.1093/oxfordjournals.schbul.a007040|issn=0586-7614|pmid=14989408}}</ref>|| Not given (N = 34) || 3.5 (not given) || 0 (not given) || Moderate – has some predictive validity (46% of those identified as prodromal by the SIPS developed schizophrenia psychosis within 6 mo.) |[https://mfr.osf.io/render?url=https://osf.io/scxyh/?action=download%26mode=render SIPS] |- | Bonn Scale for the Assessment of basic Symptoms – BSABS (Gross, 1989; Klosterkotter, Hellmich, Steinmeyer, Schultze-Lutter, 2001)<ref name=Gross1989/><ref>{{Cite journal|last=Klosterkötter|first=J.|last2=Hellmich|first2=M.|last3=Steinmeyer|first3=E. M.|last4=Schultze-Lutter|first4=F.|date=2001-02|title=Diagnosing schizophrenia in the initial prodromal phase|url=https://pubmed.ncbi.nlm.nih.gov/11177117|journal=Archives of General Psychiatry|volume=58|issue=2|pages=158–164|doi=10.1001/archpsyc.58.2.158|issn=0003-990X|pmid=11177117}}</ref>• *Cluster 1 = thought, language, perception, and motor disturbances *Cluster 2 = impaired bodily sensations *Cluster 3 = impaired tolerance to normal stress *Cluster 4 = disorders of emotion and affect including impaired thought, energy, concentration, and memory *Cluster 5 = increased emotional reactivity, impaired ability to maintain or initiate social contacts, and disturbances in nonverbal expression || (N = 160) *C1 = 0.81 *C2 = 0.50 *C3 = 0.52 *C4 = 0.57 *C5 = 0.58 || Overall = 2.4 (>=1) *C1 = 3.1 *C2 = 0.48 *C3 = 0.97 *C4 = 1.1 *C5 = 1.4 (*) || Overall = 0.03 (>=1) *C1 = 0.52 *C2 = 1.0 *C3 = 0.77 *C4 = 0.5 *C5 = 0.70 (*) || Moderate – has some predictive validity for individuals who are in the prodromal period or suspected to be in the prodromal period of schizophrenia overall, cluster 1 has best predictive accuracy and may be most useful |Not found |- |Symptom Severity Scale of the DSM5<ref>{{Cite journal|last=Ritsner|first=Michael S.|last2=Mar|first2=Maria|last3=Arbitman|first3=Marina|last4=Grinshpoon|first4=Alexander|date=2013-06-30|title=Symptom severity scale of the DSM5 for schizophrenia, and other psychotic disorders: diagnostic validity and clinical feasibility|url=https://www.sciencedirect.com/science/article/pii/S0165178113001042|journal=Psychiatry Research|language=en|volume=208|issue=1|pages=1–8|doi=10.1016/j.psychres.2013.02.029|issn=0165-1781}}</ref> |0.85 (N=314) |3.53 |0.35 |Medium: Schizophrenia versus all other psychotic disorders, but has not been studied in a variety of populations with schizophrenia as it is a relatively new measure. |[https://mfr.osf.io/render?url=https://osf.io/7hwmy/?action=download%26mode=render DSM 5 Scale] |- |Positive and Negative Syndrome Scale (PANSS)<ref>{{Cite journal|last=Kay|first=S. R.|last2=Fiszbein|first2=A.|last3=Opler|first3=L. A.|date=1987-01-01|title=The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia|url=https://academic.oup.com/schizophreniabulletin/article-lookup/doi/10.1093/schbul/13.2.261|journal=Schizophrenia Bulletin|language=en|volume=13|issue=2|pages=261–276|doi=10.1093/schbul/13.2.261|issn=0586-7614}}</ref><ref>{{Cite journal|last=Ritsner|first=Michael S.|last2=Mar|first2=Maria|last3=Arbitman|first3=Marina|last4=Grinshpoon|first4=Alexander|date=2013-06-30|title=Symptom severity scale of the DSM5 for schizophrenia, and other psychotic disorders: diagnostic validity and clinical feasibility|url=https://www.sciencedirect.com/science/article/pii/S0165178113001042|journal=Psychiatry Research|language=en|volume=208|issue=1|pages=1–8|doi=10.1016/j.psychres.2013.02.029|issn=0165-1781}}</ref> |0.91 (N=314) |N/A |N/A |Note: 45 minute clinical interview. Requires training. Attached to appendix. |Not free |} '''Note:''' ‡ Used the SCID administered by trained raters. • Used Present State Examination 9 and psychiatrist diagnosis. (*) Cutoff score for all clusters was 15% of symptoms in that cluster present (for cluster 1= 5/35 symptoms) *“LR+” refers to the change in likelihood ratio associated with a positive test score, and “LR-” is the likelihood ratio for a low score. Likelihood ratios of 1 indicate that the test result did not change impressions at all. LRs larger than 10 or smaller than .10 are frequently clinically decisive; 5 or .20 are helpful, and between 2.0 and .5 are small enough that they rarely result in clinically meaningful changes of formulation (Sackett et al., 2000). '''Search terms:''' [schizophrenia] AND [sensitivity OR specificity] AND [differential diagnosis] AND [<nowiki/>[[wikipedia:Prodrome|prodrome]]] in MedLine and PsycINFO === Interpreting schizophrenia screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for schizophrenia=== {| class="wikitable" |+ !Diagnostic Interview !Format !Age Range/ !Administration Time !Where to Access |- |Structured Clinical Interview for DSM-V (SCID)<ref>{{Cite web|url=https://www.appi.org/products/structured-clinical-interview-for-dsm-5-scid-5|title=Structured Clinical Interview for DSM-5 (SCID-5)|website=www.appi.org|accessdate=2018-03-08}}</ref> |Semi-structured interview to be administered by a clinician or an experienced rater |Adults (Ages 18+) |Varies | -Available for purchase from [https://www.appi.org/products/structured-clinical-interview-for-dsm-5-scid-5 APA Publishing] (Note: Not free) -Modified [https://mfr.osf.io/render?url=https://osf.io/x9smc/?action=download%26mode=render] (not most recent version, SCID-I) -Located on Penn Lab, See Appendix 1 for schizophrenia modules |- |Mini-International Neuropsychiatric Interview (MINI)<ref>{{Cite journal|last=Sheehan|first=D. V.|last2=Lecrubier|first2=Y.|last3=Sheehan|first3=K. H.|last4=Amorim|first4=P.|last5=Janavs|first5=J.|last6=Weiller|first6=E.|last7=Hergueta|first7=T.|last8=Baker|first8=R.|last9=Dunbar|first9=G. C.|date=1998|title=The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10|url=https://pubmed.ncbi.nlm.nih.gov/9881538|journal=The Journal of Clinical Psychiatry|volume=59 Suppl 20|pages=22–33;quiz 34–57|issn=0160-6689|pmid=9881538}}</ref> |Structured interview to be administer by a mental health professional with extensive training |Adults, also a children and adolescent version available |Mean 18.7 minutes | -Available on the [https://harmresearch.org/mini-international-neuropsychiatric-interview-mini/ Harm Research Institute] for purchase |- |- | colspan="5" style="font-size:110%; text-align:center;" |'''For Children and Adolescents Only''' |- |[[wikipedia:Kiddie_Schedule_for_Affective_Disorders_and_Schizophrenia|Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (KSADS-PL DSM-V)]] |Semi-structured interview to be administered by a health care provider or highly trained clinical researcher |Ages 6-18 |45-75 minutes |[https://www.kennedykrieger.org/sites/default/files/library/documents/faculty/ksads-dsm-5-screener.pdf PDF Version] |} ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for schizophrenia. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Severity and outcome === * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase found here]. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures see here.] ==== Clinically significant change benchmarks with common instruments for schizophrenia ==== {| class="wikitable sortable" border="1" |- | rowspan=1" style="text-align:center;font-size:130%;" | <b> Measure</b> | style="text-align:center;font-size:130%;" | '''Scale'''<b></b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut Scores*</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (Unstandardized Scores)</b> |- | colspan="2" | | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" | <b> B</b> | style="text-align:center;font-size:110%" | <b> C</b> | style="text-align:center;font-size:110%" | <b> 95%</b> | style="text-align:center;font-size:110%" | <b> 90%</b> | style="text-align:center;font-size:110%" | <b> SE_difference</b> |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms for Samples with Schizophrenia</b> |- | rowspan="3" style="text-align:center;" | <i> Positive and Negative Syndrome Scale <br> (1987 Norms)</i> | style="text-align:center;" | PANSS Positive Scale | style="text-align:center;"| 6 | style="text-align:center;"| n/a | style="text-align:center;"| n/a | style="text-align:center;"| 8.8 | style="text-align:center;"| 7.4 | style="text-align:center;"| 4.5 |- | rowspan="1" style="text-align:center;" | PANSS Negative Scale <br> | style="text-align:center;"| 8.8 | style="text-align:center;"| n/a | style="text-align:center;"| n/a | style="text-align:center;"| 7.0 | style="text-align:center;"| 5.9 | style="text-align:center;"| 3.6 |- | rowspan="1" style="text-align:center;" | PANSS General Psychopathology Scale <br> | style="text-align:center;"| 18.8 | style="text-align:center;"| n/a | style="text-align:center;"| n/a | style="text-align:center;"| 9.5 | style="text-align:center;"| 8.0 | style="text-align:center;"| 4.8 |- | rowspan="2" style="text-align:center;" | <i> Scale for the Assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS) <br> (1991 Norms)</i> | style="text-align:center;" | SAPS | style="text-align:center;"| -6.9 | style="text-align:center;"| n/a | style="text-align:center;"| n/a | style="text-align:center;"| 13.4 | style="text-align:center;"| 11.3 | style="text-align:center;"| 6.8 |- | rowspan="1" style="text-align:center;" | SANS <br> | style="text-align:center;"| 0.6 | style="text-align:center;"| n/a | style="text-align:center;"| n/a | style="text-align:center;"| 13.9 | style="text-align:center;"| 11.7 | style="text-align:center;"| 7.1 |- | rowspan="1" style="text-align:center;"| ''Social Skills (Social Functioning Scale)'' | |90.9 |268.7 |102.1 |7.2 |6.0 |3.6 |- | rowspan="1" style="text-align:center;"|''Brief Psychiatric Rating Scale (BPRS)'' | | | | | | | |} '''Note:''' “A” = Away from the clinical range, “B” = Back into the nonclinical range, “C” = Closer to the nonclinical than clinical mean. '''Note:'''&nbsp;Clinical significance may be limited for use in schizophrenia as the disorder is currently incurable and the extent to which a return to normal functioning may be less common. For this reason, some investigators have used methods other than those proposed by Jacobson and Truax (1991) to develop cut-off points (Jacobson et al. 1999). * Example: Positive and Negative Syndrome Scale (PANSS) cut-off scores of 40, 45 and 50 have been mentioned for clinically significant change for schizophrenia patients in hospital settings (Schennach et al. 2015). '''Search terms:''' [schizophrenia] AND [clinical significance OR outcomes OR change] AND [PANSS OR SWLS] in MedLine and PsycINFO === Treatment === See [[wikipedia:Management_of_schizophrenia|Management of Schizophrenia]]. ==External Resources== #[https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f1683919430 ICD-11 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) #[https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml NIMH] (information about schizophrenia) # OMIM (Online Mendelian Inheritance in Man) ##[https://www.omim.org/entry/181500?search=schizophrenia&highlight=schizophrenia 181500] == Web-based resources == '''Online Support Group'''&nbsp;for Family Members & Individuals with Schizophrenia [http://www.schizophrenia.com/coping.html Website] '''Chatrooms'''&nbsp;for Individuals with Schizophrenia: *http://www.schizophrenia-online.com/ *http://theircvillage.com/chat/ '''[http://www.schizophrenia.com General Information&nbsp;about Schizophrenia]''' == References == {{collapse top| Click here for references}} {{Reflist|2|refs= <ref name=KesslerEtAl1994>{{cite journal|last1=Kessler|first1=RC|last2=McGonagle|first2=KA|last3=Zhao|first3=S|last4=Nelson|first4=CB|last5=Hughes|first5=M|last6=Eshleman|first6=S|last7=Wittchen|first7=HU|last8=Kendler|first8=KS|title=Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.|journal=Archives of general psychiatry|date=January 1994|volume=51|issue=1|pages=8-19|pmid=8279933}}</ref> <ref name=RobinsRegiers1991>{{cite book |editor=Robins, Lee N. |editor2=Freedman, Darrel A. |title=Psychiatric disorders in America : the epidemiologic catchment area study |date=1991 |publisher=Free Press |location=New York |isbn=9780029265710}}</ref> <ref name=DumaisEtAl2010>{{cite journal|last1=Dumais|first1=A|last2=Côté|first2=G|last3=Lesage|first3=A|title=Clinical and sociodemographic profiles of male inmates with severe mental illness: a comparison with voluntarily and involuntarily hospitalized patients.|journal=Canadian journal of psychiatry. 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Supplement|date=November 1989|issue=7|pages=21-5; discussion 37-40|pmid=2695138}}</ref> <ref name=KlosterkotterEtAl2001>{{cite journal|last1=Klosterkötter|first1=J|last2=Hellmich|first2=M|last3=Steinmeyer|first3=EM|last4=Schultze-Lutter|first4=F|title=Diagnosing schizophrenia in the initial prodromal phase.|journal=Archives of general psychiatry|date=February 2001|volume=58|issue=2|pages=158-64|pmid=11177117}}</ref> }} {{collapse bottom}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] 8s1lmbd52n7galrfirjwkhi48uge99u 3 212854 2408226 2407897 2022-07-20T21:21:01Z Atcovi 276019 /* Continuing Email Discussion */ new section wikitext text/x-wiki === [https://en.wikipedia.org/wiki/User_talk:Evolution_and_evolvability My main Wikipedia usertalk page is here] === == Eukaryotic and prokaryotic gene structure == Hi Evolution and evolvability! [[WikiJournal of Medicine/Eukaryotic and prokaryotic gene structure|Eukaryotic and prokaryotic gene structure]] has been apparently completed as of 20 January 2017 and published in the [[WikiJournal of Medicine]]! Would you like this announced on our Main Page News? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 20:23, 21 January 2017 (UTC) :{{re|Marshallsumter}} That would be fantastic! Is there anything that I would need to do to facilitate that? <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:32, 22 January 2017 (UTC) == Template:Article info == There is an error in [[Template:Article info]] demonstrated on [[WikiJournal of Medicine/Diagram of the pathways of human steroidogenesis]] and [[Talk:WikiJournal of Medicine/Diagram of the pathways of human steroidogenesis]], where "expansion depth is exceeded. The error is specifically related to the <code>|accepted = 27 March 2014</code> parameter. If that line is removed, the error goes away. Please investigate. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 04:09, 12 February 2017 (UTC) ::Thanks {{u|Dave Braunschweig}}. I'll look into what's going on. It's evidently calling too many templates within templates. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 06:47, 12 February 2017 (UTC) == Template:Fig == There's an issue in [[Template:Fig]] with too many closing curly braces in a <nowiki>[[File:]]</nowiki> tag somewhere. I can't find it, though. See [[Special:LintErrors/bogus-image-options]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 00:26, 26 April 2017 (UTC) :Thank you! I'll see if I can find it. A quick search indicates that there are 886 opening and closing braces, so at least there's a matched number! I'll see if I can find an example where the template misformats, which might give a clue as to where the braces have been misplaced. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 00:43, 26 April 2017 (UTC) ::It's also possible that there's a bug in the reporting tool. There may be so many curly braces there that it got lost / confused. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:15, 27 April 2017 (UTC) :::See [https://en.wikiversity.org/w/index.php?title=Template%3AFig&type=revision&diff=1716029&oldid=1668697]. Alt needs to be conditional, and use {{tl|!}} to include the separator only when present. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 20:49, 4 August 2017 (UTC) ::::{{re|Dave Braunschweig}} Thank you! Sadly, one problem remains. The {{tl|!}} expands to a space in stead of a pipe when transcluded into a table (including in multicolumns layout. This is a problem because the multiple column layouts (like {{tl|col-begin}}) are useful for making columns that reflow into a single column on mobiles. See below for what I mean (note the link destinations): <pre>{{fig|1|Sobo 1909 639.png|capn|size=100px|link=main}}</pre> '''Correct transclusion:''' {{fig|1|Sobo 1909 639.png|capn|size=100px|link=main}} {{-}} '''Error when transcluded in table:''' {| | {{fig|1|Sobo 1909 639.png|capn|size=100px|{{!}}link=main}} |} {{clear}} You can force the separation in a table. See above. Also, I've been working on a better columns template. It's not fully tested yet, but try {{tl|Columns}}. It's better for mobile column display. We need to start moving away from tables for layout. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 17:33, 5 August 2017 (UTC) ::{{re|Dave Braunschweig}} Champion, thank you! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:15, 6 August 2017 (UTC) == Files Missing Information == Thanks for uploading files to Wikiversity. All files must have source and license information to stay at Wikiversity. The following files are missing {{tlx|Information}} and/or [[Wikiversity:License tags]], and will be deleted if the missing information is not added. See [[Wikiversity:Uploading files]] for more information. * [[:File:Vitamin D as an adjunct for acute community-acquired pneumonia among infants and children systematic review and meta-analysis.pdf]] [[User:MaintenanceBot|MaintenanceBot]] ([[User talk:MaintenanceBot|discuss]] • [[Special:Contributions/MaintenanceBot|contribs]]) 00:42, 30 June 2017 (UTC) :I added {{tl|Cc-by-sa-3.0}}. If that is incorrect, please update. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 00:45, 30 June 2017 (UTC) ::Thanks! Have edited to CC-BY-4. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 01:00, 30 June 2017 (UTC) == Curator Status == Would you have any interest in [[Wikiversity:Curators]] status? I'd be happy to nominate you. It provides extra tools that can make some of the editing you do easier. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:04, 14 October 2017 (UTC) :{{re|Dave Braunschweig}} Thank you for your suggestion. I'll read up more on that. It seems that many of those tools would be very useful. My only hesitation is that I've only contributed to a very specific corner of Wikiversity! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 01:35, 15 October 2017 (UTC) ::{{re|Dave Braunschweig}} I've now lodged my [[Wikiversity:Candidates for Custodianship#Evolution and evolvability .28talk .7C email .7C contribs .7C stats.29|application]] for Probationary Custodianship. If you'd consider being my mentor in this, I'd greatly appreciate your technical expertise and wiki experience. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 10:52, 25 October 2017 (UTC) :::Done. Please monitor the page for questions and discussion. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:55, 25 October 2017 (UTC) You are now a curator. Congratulations! Please visit [[Wikiversity:Support staff]] and add yourself to the list. Then visit [[Special:SpecialPages]] and individual page menus and check out the new tools. Let me know whenever you have questions. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:46, 30 October 2017 (UTC) :{{re|Dave Braunschweig}} Thank you for your original recommendation to apply, and for the subsequent support. It's good to be aboard. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 23:54, 30 October 2017 (UTC) == Editor in chief == Hi Thomas! I recently took on a new full-time job that is leaving me little time for wikis. I was trusting that sooner or later I would find the time and energy to catch up with all the changes going on in the WJS, but truth is I'm not seeing that moment coming any time soon. Therefore, I'd like to offer you the title of "editor in chief". I also considered [[User:Marshallsumter]], but although he's been the most active reviewer, you've been the most active editor, so I think that you're the most appropriate person for "editor in chief". Let me know if you want to take on this responsibility, and I'll be happy to update the board accordingly. Kind regards, --[[User:Sophivorus|Felipe]] ([[User talk:Sophivorus|discuss]] • [[Special:Contributions/Sophivorus|contribs]]) 00:54, 26 October 2017 (UTC) :@{{u|Sophivorus|Felipe}}: Thank you for your message. I Would be very happy to be Editor in Chief. Once the journal gets going and bylaws have been ratified we can hold a formal vote for Eic and assistant EiC roles. I hope that you'll stay involved, even if you can't devote the time you used to. Similarly, reaching out to potential contributors may be an effective 'time investment' if you happen to know people who might be interested in being involved. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:12, 27 October 2017 (UTC) ::Thanks for relieving me {{u|Evolution and evolvability|Thomas}}, I just updated the board. I'll definitely stick around and contribute when I can. Cheers! --[[User:Sophivorus|Felipe]] ([[User talk:Sophivorus|discuss]] • [[Special:Contributions/Sophivorus|contribs]]) 03:16, 28 October 2017 (UTC) == Current reviews == Hi Evolution and evolvability! As editor-in-chief, please feel free to review my reviews and make what ever changes or contacts you believe are necessary or appropriate to move a submission to acceptance! Also, I believe WikiJournal of Science could allow submission of original research as well. What do you think? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:42, 28 October 2017 (UTC) ::{{re|Marshallsumter}} Thanks for your great work on those! Could I check if there were any other reviewers for [[Dialectic_algorithm]] or [[Space_(mathematics)]]? If there's only one, would you mind contacting as few other people to ask them to be an external reviewer ([https://drive.google.com/file/d/0B4LQzkvkbO9YWmZjc0NvLU14Z2c/view?usp=sharing here's an example email template])? A good way is to look at the contact addresses for corresponding authors on cited papersm and/or ask the author for suggestions. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 05:53, 29 October 2017 (UTC) :::{{re|Evolution and evolvability}} "Could I check if there were any other reviewers for [[Dialectic algorithm]]?" Of course! Depending on your point of view, if you check out the [[Talk:Dialectic algorithm|discuss]] page, you'll read constructive reviewing by [[User:Koavf|Justin (<span style="color:grey">ko'''a'''vf</span>)]]<span style="color:red">❤[[User talk:Koavf|T]]☮[[Special:Contributions/Koavf|C]]☺[[Special:Emailuser/Koavf|M]]☯</span> prior to submission to WikiJournal of Science. This user may also be willing to add an additional review if you ask or believe more is needed. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 03:33, 30 October 2017 (UTC) :::{{re|Evolution and evolvability}} "Could I check if there were any other reviewers for [[Space_(mathematics)]]?" The Wikipedia version has been reviewed on [[w:Talk:Space (mathematics)]] also prior to submission. The expanded version per my review is here. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 03:48, 30 October 2017 (UTC). ::::{{re|Marshallsumter}} Excellent work, thanks. In order to be thorough I've also contacted a set of external academics to review them. I've used authors who have published in the relevant field (G-scholar search) and authors of references in: [[w:Logic_and_dialectic]], [[w:Argumentation_framework]], [[w:Argumentation_theory]] and [[w:Logic_of_argumentation]], as well as the various categories of [[w:Space_(mathematics)#Types_of_spaces]]. I've emailed you the list so that you have them on file. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 13:07, 30 October 2017 (UTC) ==Journal== I did an edit to the page about the journal related to humanities that you created. You stated that review would be done by medical experts. I inserted 'recognized' rather than medical. Best Regards, [[User:Barbara (WVS)|Barbara (WVS)]] ([[User talk:Barbara (WVS)|discuss]] • [[Special:Contributions/Barbara (WVS)|contribs]]) 13:57, 30 October 2017 (UTC) :{{re|Barbara (WVS)}} Thank you for picking up the oversight! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 23:36, 30 October 2017 (UTC) ::Not a problem. [[User:Barbara (WVS)|Barbara (WVS)]] ([[User talk:Barbara (WVS)|discuss]] • [[Special:Contributions/Barbara (WVS)|contribs]]) 18:17, 7 November 2017 (UTC) == "Article info" template == As far as I understand, nearly all the talk page to a submission is now just one parameter "review" to this template; and probably this is why we cannot edit sections (such as "Second review" or "Editorial comment") separately; a bit inconvenient. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 07:44, 4 November 2017 (UTC) ::You're right. It's an artefact of the way I first built the template. It should be solvable so I'll put some time into fixing it tomorrow. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:05, 4 November 2017 (UTC) ::::{{re|Tsirel}} Thanks for bringing this to my attention. I think I've addressed the issue now, but please let me know if you notice any strange behaviours or errors! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:02, 7 November 2017 (UTC) == The goal of WikiJournals == It seems, I misunderstood the goal of this movement. I believed that, born on Wikiversity, it intends to create learning resources. But now I see that it intends rather to create encyclopedic articles (and put them on Wikipedia). Hmmm... Wikipedia is already successful; Wikiversity is not. I rather wait for something like that but Wikiversity integrated. Sorry. Really, I do not understand, who needs peer reviewing for creating collections of excerpts from already existing reliable sources. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 12:01, 8 November 2017 (UTC) :: {{re|Tsirel}} Hi, I completely sympathise with the confusion. The whole concept of WikiJournals is still finding its feet. There are articles that have been published focused primarily on providing wikiversity teaching resources ([[WikiJournal of Medicine/Acute gastrointestinal bleeding from a chronic cause: a teaching case report|example]]), and some that are published as basically stand alone papers that don't yet integrate into any wikimedia project at all ([[WikiJournal of Medicine/Vitamin D as an adjunct for acute community-acquired pneumonia among infants and children: systematic review and meta-analysis|example]]). However, I think that there is a useful place for peer review of encyclopedic articles ([[WikiJournal of Medicine/The Hippocampus|example]]). Like writing an [[w:Review article|academic review article]], even summarised information can benefit from having independent experts. For example: ::# It ensures that the article is up to date and hasn't missed developments in the field ::# Non-wikipedian experts can be engaged as external peer reviewers, when they otherwise would have never contributed to wikimedia content ::# It gives readers a stable version of record to check that has an additional level of authoritativeness ::Wikipedia still suffers from a lack of credibility and this form of academic peer review is one way of improving it. I think that the space in mathematics article is ideal for re-integrating into Wikipedia as well as being a standalone teaching item. If you would like to also create more wikiversity-focused content, you could also create a second, textbook/course-material version for teaching the topic in a more step-by-step manner. Indeed, the journal would be be compatible with additional versions targeted at specific audiences, e.g.: ::* "Introduction to spaces in mathematics" - similar to [[w:Introduction to viruses|Introduction to viruses]] on wikipedia ::* "Spaces in mathematics (in simple english)" - similar to [https://simple.wikipedia.org/wiki/Virus Virus] in simple-english wikipedia ::* "Spaces in mathematics (for secondary school students)" ::I'll attempt clarify a bit better tomorrow! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:56, 8 November 2017 (UTC) :::Thank you for the clarification. I am glad to know that different kinds of articles are allowed in WikiJournals (at least, for now). :::Yes, I see: the problem of credibility (of scientific Wikipedia articles) can be alleviated by WikiJournal articles included into Wikipedia. :::However, the problem of [[w:User talk:Jimbo_Wales/Archive_224#Science and math articles|inaccessibility]] (of scientific Wikipedia articles) needs another approach (I think so). It cannot be solved inside Wikipedia. But it could be solved (well, alleviated) by ''attaching'' explanatory articles, published in WikiJournals, to Wikipedia. I mean, not including them into Wikipedia, but linking them from relevant Wikipedia articles. :::This option is rarely used, but here is a recent example: the Wikipedia article "[[w:Representation theory of the Lorentz group]]" contains (in the end of the lead, and again in Sect. 3.2 "Technical introduction to finite-dimensional representation theory") a link to Wikiversity article "[[Representation theory of the Lorentz group]]". The reason is mostly "the blue link hell" problem, see [[w:Talk:Representation theory of the Lorentz group|arguments]] of [[w:User:YohanN7|the most active contributor]] there. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 18:21, 9 November 2017 (UTC) ::::{{re|Tsirel}} You make a good point that Wikipedia typically has a single article on a topic that is ''supposed'' to cater to all audiences simultaneously. In reality this is extremely difficult, and articles often tent towards begin highly technical (as the discussions you linked to described well). The "[[w:Introduction to viruses|introduction to]]" or "[https://simple.wikipedia.org/wiki/Virus simple English]" articles are one possible solution. Another solution that I've seen is to have a non-technical summary section (e.g. in the [[wikipedia:Higgs_boson#Non-technical_summary|Higgs Boson]]). Your idea of also having attached explanatory notes is a also good one, and could be done in WikiJournals in a step-by-step textbook style article. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 03:09, 25 November 2017 (UTC) :::::"Introduction to" idea was discussed on [[w:WT:WPM]] several times, and rejected as content forking that can be tolerated only as a rare exception (namely, only for Intro to General relativity and Intro to Quantum mechanics). :::::"Simple English"? Hmmm... I do not know what is considered "simple English", but I doubt that it can be something like <small>"Every point of the affine space is its intersection with a one-dimensional linear subspace (line through the origin) of the (n+1)-dimensional linear space. However, some one-dimensional subspaces are parallel to the affine space; in some sense, they intersect it at infinity."</small> or <small>"Away from the origin, the quotient by the group action identifies finite sets of equally spaced points on a circle. But at the origin, the circle consists of only a single point, the origin itself, and the group action fixes this point."</small> Or can it? :::::"Non-technical summary section"? Probably it may contain something like <small>"The type of space that underlies most modern algebraic geometry was introduced by Alexander Grothendieck and is called a scheme. One of the building blocks of a scheme is a topological space."</small> but hardly these not-so-simle-English phrases above. :::::Also, look (again) at my [[w:Conditioning (probability)]]. It is an explanatory essay, but it consists mostly of formulas. Surely not a simple English, nor a non-technical summary. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 11:04, 25 November 2017 (UTC) :::::Another well-known hard problem with math on WP is, examples. It is impossible to explain mathematics without many examples. But on WP an example is, almost inevitably, either Original Research, or Copyright Violation (since only rarely a single example appears in many textbooks). [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 11:46, 25 November 2017 (UTC) {{od}} {{re|Tsirel}} Very good points. I think for the [[Spaces in mathematics|Spaces in Mathematics]] article, the decider for its final style and format is your preferences for whether you want it to be an updated and improved version of the Wikipedia article that is then re-integrated into Wikipedia (like [[w:Rotavirus|Rotavirus]], etc), or whether you'd prefer it to be a companion piece to the Wikipedia article that is a teaching or explanatory aid. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:48, 4 December 2017 (UTC) :I definitely prefer "a companion piece to the Wikipedia article that is a teaching or explanatory aid". Here is why. :What really is to be re-integrated? Ozob's contribution (mostly inspired by the anonymous referee) is already there. My "Spaces and structures" and "Mathematical spaces in science and engineering" (mostly inspired by Marshall Sumter)? Yes, these could be added to WP, which however would be far not a historic event, anyway. :In contrast, "a companion piece" precedent, if gets traction, has a chance to be a historic event. Here is why. :Wikipedia's goal "to inform, but not teach, wide public" is definitely unattainable in mathematics, and maybe in hard sciences. You cannot inform wide public that "a continuous function on a closed interval is bounded" without teaching the meaning of these words in this context, with informal explanations of the intuition, examples etc. :For now, mathematical articles on WP either violate the rules, or rightly revolt people; usually do both, as a compromise. :If "Spaces in Mathematics" will become a companion piece linked from "Space (mathematics)", let the latter be challenged, the "types of spaces" section removed, etc. I could be the first to attack it, though I'm afraid others would revert me. Anyway, then the tight knot could begin to unravel, globally. And the expertise of authors, referees and editors of WikiJSci could be used in full strength. Verifiability in the (very restrictive) WP sense need not hold for articles, lectures, textbooks, essays etc (since these are not something that "anyone can edit"). [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 07:17, 4 December 2017 (UTC) == An observation about mathematics and Wikipedia rules == There are very few featured articles on mathematics in Wikipedia. Taking the list from [[w:WP:WPM#Recognized content]], excluding biographies, history, and articles that are more physical than mathematical, I got about 9 articles (out of about 16,000). Now, looking at [[w:1 − 2 + 3 − 4 + ⋯|one of most interesting to me]] of these 9, I see "citation needed" 3 times, and "clarification needed" once. Well, others are "clean" (probably); but two of them are very elementary. Anyway, generally, mathematicians prefer not to pursue the almost infeasible goal of being featured. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 21:46, 30 November 2017 (UTC) == Thank you for your work on the Wiki Journal of Science == I will delete all reference to WJS in [[How_things_work_college_course/Quantum_mechanics_timeline]], after [https://en.wikiversity.org/w/index.php?title=How_things_work_college_course%2FQuantum_mechanics_timeline&type=revision&diff=1786688&oldid=1707257 your decision] to decline it. I have had many article submissions declined in my life, but this is the first time I immediately concurred with the journal's decision (although it is not uncommon for me to agree with such decisions after pondering things a bit.) I copied the format for what is now the WJS from the WJM because I strongly believe in the importance of such journals. But I teach full time, and need to pursue a slightly different track, which is to give students graded credit for improving a course. OpenStax college has provided [[w:Open educational resources|OER]] textbooks most of my courses, but unfortunately without that labor-saving exam bank, I expect that only a limited number of instructors will be adopting these textbooks. To see an example of how we can fix this, see [[:File:Anonymous Life in the Universe.pdf|this student effort]]. When I see a student effort appropriate for WJS I will certainly recommend that they submit an article. --[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 15:30, 3 December 2017 (UTC) :{{re|Guy vandegrift}} Thank you for your message. I realise that the project has evolved significantly from its original inception. Although the journal aspect ended up matching more closely to WikiJMed, I see the value of what you're working towards. Very best of luck with your courses, and I look forward to any student works that get submitted. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:33, 3 December 2017 (UTC) == Radiocarbon dating == Have you or Brian Whalley found a second reviewer? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 19:50, 1 January 2018 (UTC) :{{re|Marshallsumter}} Sadly not. [[User:Jacknunn|Jack Nunn]] has also offered to ask a suitably qualified contact of his, but any additional referees that you're able to gather would be very helpful. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:51, 2 January 2018 (UTC) ::I've sent an email via ResearchGate to Professor A. J. Timothy Jull, Editor-in-Chief, of ''Radiocarbon'' to ask if he or one or two of his Editorial Board members would be willing to submit a review or two, or suggest possible reviewers. I'll let you know the results. I also gave him the url here for your talk page. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 17:27, 2 January 2018 (UTC) == CSS == Just FYI. When you imported the Wikipedia versions of Template:Navbox, Template:Navbar, Module:Navbox, and Module:Navbar, it broke the local display of those items. I didn't figure out why or how until this week, and I wasn't able to fix it until this evening. Those templates depend on custom CSS styles that were in [[Wikipedia:MediaWiki:Common.css]] but were not included here. I copied the Wikipedia Common.css file in it's entirety and loaded it as the first thing in our [[MediaWiki:Common.css]] file. Any local styles that come after will override Wikipedia settings. There's obviously going to be redundancy, but unless someone is willing to go through and clean up local styles we don't need, this is the best we can do. I had never encountered this before, but it's now something to be aware of. When replacing local templates, we need to be sure to use something that transcludes the template and view before and after import to make sure it doesn't break anything or miss styling. [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 04:17, 6 January 2018 (UTC) :{{re|Dave Braunschweig}} Thank you for notifying me. So sorry that it messed up some of the existing CSS. I'll check more carefully whether imported templates and modules overwrite existing elements from now on. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 12:42, 6 January 2018 (UTC) == Editorial board tends to infinity? == "Section 3. Appointment<br> (a) The number of Editorial Board Members of Wiki.J.Sci. should be kept at a minimum of 10 and a maximum of 20."<br> (From Bylaws#ARTICLE_III). Nevertheless I see 25 members. Do I miss something? [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 09:47, 21 April 2018 (UTC) ::{{re|Tsirel}} Thank you for notifying me! It had completely escaped my mind that we'd put size limits in the bylaws. I shall absolutely bring that up for discussion. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 12:14, 21 April 2018 (UTC) ::{{re|Tsirel}} I suggest that we change the bylaws and have at least 30 people - I'm on the Editorial Board for another journal and that is a very long list - the more the merrier! (https://researchinvolvement.biomedcentral.com/about/editorial-board) [[User:Jacknunn|Jacknunn]] ([[User talk:Jacknunn|discuss]] • [[Special:Contributions/Jacknunn|contribs]]) 13:35, 30 January 2019 (UTC) == Sorry about misspelling your nickname== I called you Evo^2, when the ampersand suggests the simpler 2Evo. See https://en.wikiversity.org/w/index.php?title=Talk%3AWikiJournal_of_Science&type=revision&diff=1859146&oldid=1859076 -[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 01:18, 25 April 2018 (UTC) :{{re~Guy vandegrift}} Heh, I missed this when you first posted it - Looks like the the untaken options are rapidly running out: https://www.biosculpture.com.au/products/evo2/ https://www.evosq.co/ == I have begun to seriously edit Draft: A card game for Bell's theorem and its loopholes == I started with the comments from the third reviewer because their effort was the most meticulous. I spent a lot of time on the first paragraph and will take a 24 hour break and to other things while I ponder this. Feel free to comment if you have time. But if you are busy, do not hesitate to wait a bit. --[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 22:38, 2 May 2018 (UTC) *See [[Draft talk:A card game for Bell's theorem and its loopholes#Author's_final_(?)_response_begins_here.]] *See also [[Draft:A card game for Bell's theorem and its loopholes/Guy vandegrift]]--[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 22:44, 2 May 2018 (UTC) ::{{re|Guy vandegrift}} Thanks for the note. I'll read through the comments as they stand this evening. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:28, 6 May 2018 (UTC) == [[ShK toxin: history, structure and therapeutic applications for autoimmune diseases]] == Should we include doi links in the references? [[User:OhanaUnited|<b>{{font|color=#0000FF|OhanaUnited}}</b>]][[User talk:OhanaUnited|<b>{{font|color=green|^{Talk page}}}</b>]] 02:21, 18 May 2018 (UTC) :{{re|OhanaUnited}} Yes, when possible. I think I citoid generated a few from the PMIDs and it doesn't always find the doi. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:09, 18 May 2018 (UTC) :: I believe the author added some references[https://en.wikiversity.org/w/index.php?title=ShK_toxin%3A_history%2C_structure_and_therapeutic_applications_for_autoimmune_diseases&type=revision&diff=1867672&oldid=1867515] (including at least one that was identified as unused). And now it messes up the numbering of the reference names. [[User:OhanaUnited|<b>{{font|color=#0000FF|OhanaUnited}}</b>]][[User talk:OhanaUnited|<b>{{font|color=green|^{Talk page}}}</b>]] 21:15, 19 May 2018 (UTC) ::: Thank you for letting me know. I've sent the authors an email to explain the cite function. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:17, 20 May 2018 (UTC) == WikiJournal Main Page Representation == Any thoughts on how to add WikiJournal to [[Wikiversity:Main Page]]? -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 15:08, 10 June 2018 (UTC) :{{re|Dave Braunschweig}} So currently articles are mentioned in the [[news]] section, but I'd love a permanent presence on the main page. Do you have an idea of how much real-estate on the mainpage you'd think appropriate? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:40, 11 June 2018 (UTC) ::There are a variety of options available. WikiJournals could be added to the banner. Individual WikiJournals could be added as Featured Projects and Educational Pictures. With some type of redesign, a separate block could be added for WikiJournals, similar to either the Wikipedia or Wikibooks main pages. I don't want to limit creativity. Something should certainly be done. What may depend as much on available time to redesign or add content as anything else. I've got a lot on my plate for the summer, so if it's up to me, I would just be able to add WikiJournals to the banner. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:49, 11 June 2018 (UTC) :::{{re|Dave Braunschweig}} Thanks! I'll draft a possible template later this week. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 03:07, 12 June 2018 (UTC) ::::{{re|Dave Braunschweig}} I've been experimenting with a few possibilities at [[Main_Page/Journals]]. What to you reckon? I think it best to omit the journal logos, but perhaps include a random selection from a gallery of images? Maybe a link to random article from the back-catalogue? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 04:24, 27 June 2018 (UTC) :::::You can plug it into [[Wikiversity:Main_Page/Sandbox]] to figure out the layout. Visuals are good, something that changes every day is also good. At some point I'd like to switch the main page to a grid / flexbox design. Maybe this is a good excuse for doing that. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:33, 28 June 2018 (UTC) ::::::{{re|Dave Braunschweig}} I agree, flexbox formatting is amazing (I finally got around to using it for the menu tabs of {{tlx|article info}} so that they can be read on mobiles). There have also been some developments over at Wikipedia in [[wikipedia:Wikipedia:WikiProject_Portals|automated templates for portals]]. I've done some experiments in [[Wikiversity:Main_Page/Sandbox]]. Still not certain over the best layout. probably 33% width or 50% width will be best. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:08, 28 June 2018 (UTC) {{re|Dave Braunschweig}} I've had a go at a flex box based implementation in the [[Wikiversity:Main_Page/Sandbox]] now that I've sort of got the hang of it from working on [[Template:WikiJMed formats]]. Have a look and see what you think. It's not perfect, but shouldn't need too much further tweaking! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 09:11, 6 July 2018 (UTC) :I wonder if a two-column layout, similar to [[Wikipedia:Main Page]] would be better. There's something about the current flex design that isn't working correctly with image overlap. On my screen today, News is covering 15% of The Last Supper. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:51, 7 July 2018 (UTC) :Two-column seems better from a mobile perspective. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 01:44, 8 July 2018 (UTC) == Wikipedia links == I've created [[WikiJournal_Preprints/Ice_drilling|a preprint for ice drilling]], just by pasting in the Wikipedia wikitext, but I can see a lot of tweaking is needed. For example, the links need to change from e.g. <nowiki>[[glacier]] to [[wikipedia:glacier|glacier]]</nowiki>. Is there a script for this, or does one have to tweak each by hand? And is there a checklist of other changes that need to be made? [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 12:54, 23 June 2018 (UTC) :{{re|Mike Christie}} One of our next projects is sorting out an automated way to convert wikilinks to and files into the {{tlx|fig}} format. Currently the figures have to be done manually, but the wikilinks are switched by find-replace with regular expressions: :#<code><nowiki>\[\[([^\|]*?)\]\]</nowiki></code> replace with <code><nowiki>[[w:\1|\1]]</nowiki></code> :#<code><nowiki>\[\[([^\:]*?)\]\]</nowiki></code> replace with <code><nowiki>[[w:\1]]</nowiki></code> :Would you be able to update the information in the article info template at the top and update the fig formatting (most important is the attribution paramter). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:59, 23 June 2018 (UTC) ::Will do; have had to work this weekend and am away next weekend so I will try to get it done one night this week. Thanks for the wikilink fix. [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 20:42, 24 June 2018 (UTC) :::Done. I've submitted the authorship declaration; let me know anything else I need to do. Thanks. [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 10:20, 28 June 2018 (UTC) == Custodianship == Congratulations! You are now a custodian! You should see more tools in [[Special:SpecialPages]]. See [[Wikiversity:Custodian Mentorship]] for a list of custodian skills you should become comfortable with. First up are the following: # Edit [[MediaWiki:Sitenotice]] and clear the current site notice. # Edit [[Wikiversity:Support staff]] and update your role. Let me know whenever you have any questions. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:22, 24 June 2018 (UTC) :{{re|Dave Braunschweig}} The documentation is clear so far, but I'll message you if I've any questions. Thank you for your help so far, and as I said in the application, I aim to start out particularly cautious so as not to break anything. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:44, 24 June 2018 (UTC) == Image scaling == Hello. Trouble with display of image at main WikiJournal of Medicine (COPE logo for WikiJMed) - it is displaying in too large a way despite specifying 80px in template. [[User:RubberBandHoot|RubberBandHoot]] ([[User talk:RubberBandHoot|discuss]] • [[Special:Contributions/RubberBandHoot|contribs]]) 02:09, 18 November 2018 (UTC) :{{re|RubberBandHoot}} Thanks for letting me know! The issue seems to be because the {{tlx|WikiJMed_right_menu}} is still built as a table, rather than using the more robust css div formatting. I've used a simpler type of image formatting, which seems to work better. Eventually, I'll update the template's formatting which should make it more future-proof. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:23, 18 November 2018 (UTC) ::{{re|Evolution and evolvability|T.Shafee(Evo&#65120;Evo)}}. Thank you. [[User:RubberBandHoot|RubberBandHoot]] ([[User talk:RubberBandHoot|discuss]] • [[Special:Contributions/RubberBandHoot|contribs]]) 12:53, 18 November 2018 (UTC) == second peer review == Hello Dr. Shafee, just wanted to let you know Ive done the second peer review[https://en.wikiversity.org/wiki/Talk:WikiJournal_Preprints/West_African_Ebola_virus_epidemic] however [[WikiJournal_of_Medicine/Potential_upcoming_articles]] the 'stage' number doesn't reflect that yet, thanks--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:50, 15 December 2018 (UTC) ::{{re|Ozzie10aaaa}} - updated! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:09, 15 December 2018 (UTC) :::thanks--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 23:17, 15 December 2018 (UTC) ===further reviews=== Hi Dr. Shafee, just wanted to let you know Ive done both reviews for [[Talk:WikiJournal_Preprints/Hepatitis_E]] and [[Talk:WikiJournal_Preprints/Dyslexia]] however [[WikiJournal_of_Medicine/Potential_upcoming_articles]] the 'stage' number doesn't reflect that yet, thanks (and Merry Xmas!)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 21:00, 23 December 2018 (UTC) :{{re|Ozzie10aaaa}} Thanks for letting me know! I've updated the tracking table. We are expecting 1-2 more reviews for each of the articles in January. Happy New Year! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:38, 31 December 2018 (UTC) ::thank you(Happy New Year to you!)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 11:36, 31 December 2018 (UTC) :::Thank you Thomas and [[User:Ozzie10aaaa|Ozzie10aaaa]], and Happy New Year! [[User:Mikael Häggström|Mikael Häggström]] ([[User talk:Mikael Häggström|discuss]] • [[Special:Contributions/Mikael Häggström|contribs]]) 15:32, 31 December 2018 (UTC) ===final review=== Hi Dr. Shafee ,[[WikiJournal Preprints/Western African Ebola virus epidemic]]..done, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 03:08, 14 January 2019 (UTC) :[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Potential_upcoming_articles&diff=1965407&oldid=1964778]thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:26, 14 January 2019 (UTC) ===Hep E, final review=== Dr. Shafee, sorry to bother you however I was going over [https://upload.wikimedia.org/wikiversity/en/b/b2/WikiJournal_Preprints_Hepatitis_E_corr._pischke.pdf]and aside from a modest(13) amount of circles(red), it gives little in the way of what the reviewer wants,I suppose I could assume to check references to the statements but upon looking at the section on ''classification'' there are 'two circles' in no particular area that don't seem to indicate anything at all?...please advise, thank you (I have 'clicked' each circle with my mouse, not certain how this works)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 14:50, 15 January 2019 (UTC) *<u>have figured out, downloaded on PDF and then comments appear</u>, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 18:01, 15 January 2019 (UTC) :*{{re|Ozzie10aaaa}} Good point - it's not immediately obvious to look for the annotations in a PDF. I've been trying to find a way to export them so that they can be pasted in the Wikimarkup as well, but I've not yet found a way. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:30, 15 January 2019 (UTC) ::*[[WikiJournal Preprints/Hepatitis E]]...done, thank you Dr.Shafee--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 02:06, 16 January 2019 (UTC) :::*Thanks. I'll let you know when the next steps are done on our end. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:29, 16 January 2019 (UTC) ::::Dr. Shafee, done (again)[https://en.wikiversity.org/w/index.php?title=Talk:WikiJournal_Preprints/Hepatitis_E&diff=1966248&oldid=1965957] thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 02:06, 17 January 2019 (UTC) :::::[[Talk:WikiJournal_Preprints/Hepatitis_E#Editorial_comments]] done--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:18, 30 January 2019 (UTC) ===Ebola=== Dr.Shafee, done [[Talk:WikiJournal Preprints/Western African Ebola virus epidemic]], thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 05:19, 23 January 2019 (UTC) :Done [https://en.wikiversity.org/w/index.php?title=Talk:WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1969876&oldid=1969748], thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 07:39, 27 January 2019 (UTC) ::{{re|Ozzie10aaaa}} Thanks. One final minor thing: There are a mix of {{tlx|Cite_web}} and {{tlx|Cite_neews}} templates used used for WHO, BBC etc. Would it be sensible to distinguish different types of source with {{tlx|Cite_web}}/{{tlx|Cite_report}}/{{tlx|Cite_news}}? Not vital, but could be useful for distinguishing in the metadata. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:13, 31 January 2019 (UTC) :::The logical answer is yes, it would because they are different {{tlx|Cite_web}}/{{tlx|Cite_report}}/{{tlx|Cite_news}}, how should we proceed?--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 05:28, 31 January 2019 (UTC) ====per suggestion==== Dr Shafee per your email, Ive done the following: 1. have added the reference {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983339&oldid=1970572 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} 2. have gone thru the indicated 'media' references- :*'''26,28,29''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983345&oldid=1983342 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} :*'''36''', reference was simply redone to <u>the direct link</u> {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983353&oldid=1983345 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}}...''Doctors Without Borders'' which is a NGO. :*'''42''',{{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983361&oldid=1983353 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} :*'''47''' replaced with [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00259-5/fulltext The Lancet Post Ebola syndrome] :*'''54''', '''55''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983557&oldid=1983556 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''56''' reference/text <u>deleted</u> [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983556&oldid=1983490 did not add significantly to paragraph] :*'''61''', '''62''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983559&oldid=1983557 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''69''' replaced <u>with United nations</u> {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983581&oldid=1983559 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''74-79''' - have slightly altered as follows (''Resistance to interventions by health officials among the Guinean population remained greater than in Sierra Leone and Liberia, per media reports, raising concerns over its impact on ongoing efforts to halt the epidemic; in mid-March, there were 95 new cases and on 28 March, and a 45-day "health emergency" was declared in 5 regions of the country.[71][72] On 22 May, the WHO reported another rise in cases, per media reports,[73] which was believed to have been due to funeral transmissions;[74] on 25 May, six persons were placed in prison isolation after they were found travelling with the corpse of an individual who had died of the disease,[75] on 1 June, it was reported that violent protests in a north Guinean town at the border with Guinea-Bissau had caused the Red Cross to withdraw its workers.[76] '') diffs are available at history[https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&action=history] :*'''81''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983594&oldid=1983591 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''84''' ? :*'''85''' was replaced with {{cite web |title=Ebola Situation Report - 11 November 2015 {{!}} Ebola |url=http://apps.who.int/ebola/current-situation/ebola-situation-report-11-november-2015 |website=apps.who.int |accessdate=6 March 2019}} :*'''86''', '''87''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983606&oldid=1983605 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''90''', '''92''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983611&oldid=1983606 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}}...deleted reference 92/minor text :*'''93'''? :*'''94'''? (same sentence) :*'''95, 96, 98, 99''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983639&oldid=1983635 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} 3. have trimmed '''50''' and '''58''' press release {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983341&oldid=1983339 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} and {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=next&oldid=1983341 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} I want to thank you for your kind suggestions--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 17:26, 6 March 2019 (UTC) == Lint Errors == See [[Special:LintErrors/misc-tidy-replacement-issues]]. There are issues in several of the WikiJournal templates. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 03:10, 28 December 2018 (UTC) :{{re|Dave Braunschweig}} Thanks. I've tracked the div-span-flip error to the {{tlx|WikiJournal_top_menu}} template. Should be easy to fix once I root it out within that template. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:26, 28 December 2018 (UTC) ::{{re|Dave Braunschweig}} Fixed. It was a set of spans in the {{tlx|WikiJournal_top_menu_bar}} and {{tlx|Annotated_image_4}} templates. I've manually purged a few pages to check that it also fixes the downstream templates and pages. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:58, 29 December 2018 (UTC) See [[Special:LintErrors/html5-misnesting]]. There is an issue in [[Template:Editor's comments]]. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 03:12, 2 April 2019 (UTC) ==[[Lysenin]] article== Thomas, the article needs thorough copy-editing. Someone tagged it for citation style but it's not unclear, just not in any template. The article is written assuming considerable knowledge of cell biology and might need quite substantial glossing to make it easier to read. I've added numerous wikilinks and fixed a few bits of English that urgently needed attention, but much more is needed. Cheers, Ian [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 09:14, 6 February 2019 (UTC) :{{re|Chiswick Chap}} Good point. Upon re-reading I see what you mean about the over-technicality - that is definitely something the author can address. Would you be happy to add a comment to the submission's talkpage? The language aspects often need assistance from others, since the author is probably working at the limit of their English skills. It would good to do at least a quick copyedit run before contacting peer reviewers. Otherwise I'll summarise and add to mine. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:26, 6 February 2019 (UTC) :: OK, I've added a comment and made a (very) preliminary copy-edit of the article. --[[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 01:56, 7 February 2019 (UTC) == Final review == Dr, Shafee I noticed that the Dyslexia peer-review has been indicated for sometime in February [[WikiJournal_of_Medicine/Potential_upcoming_articles]], was wondering if there might be a difficulty with it since its almost the end of the month, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:32, 21 February 2019 (UTC) :{{re|Ozzie10aaaa}} Thanks for the note. I'll check with its [[WikiJournal of Medicine/Potential upcoming articles|review coordinators]] (Eric Youngstrom, Jitendra Kumar Sinha). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:04, 8 March 2019 (UTC) ::thank you, Dr Shafee, I am watching the article in question for any updates that need to be addressed... thank you again--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 13:46, 21 March 2019 (UTC) == tl:Cite book lua error == I noticed that you imported newer revisions of {{tl|Cite book}}. There is a "lua error" which is triggered by "coauthors=last, first" and the error goes away if the name is removed. I'm not sure what is causing the or how to fix it. The error is visible in Example 1 at the template page. --[[User:Mu301|mikeu]] ^{[[User talk:Mu301|talk]]} 18:10, 10 March 2019 (UTC) :{{re|Mu301}} I've had a look at the relevant line of [[Module:Citation/CS1]] and can't find what's causing the error, so I've asked for assistance over at the MediaWiki support desk ([https://www.mediawiki.org/wiki/Topic:Uwduy1hmnz6taq9d Topic:Uwduy1hmnz6taq9d]). Will aim to get fixed ASAP. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:22, 21 March 2019 (UTC) I noticed a similar error in {{tl|coord}} which I have [https://en.wikiversity.org/w/index.php?title=Template:Coord&diff=1992448&oldid=1951967 temporarily downrev'd to an earlier version]]. I've brought up the topic of template imports at [[Wikiversity:Colloquium#template_import]]. I'll follow up there. I'm a little concerned about the long term maintainability of these imported templates. --[[User:Mu301|mikeu]] ^{[[User talk:Mu301|talk]]} 11:51, 30 March 2019 (UTC) == WikiJournal preprints/Ice drilling technology == Hi Evolution and evolvability! Professor Taylor is mentioning in his follow up that the original title "Ice drilling" or another alternative suggested by the authors "Ice drilling methods" is okay. Should we give the authors time to reconsider? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:25, 9 April 2019 (UTC) == Widgiemoolthalite et al. == Hey Evolution and evolvability, Thanks for all your work on the WikiJournal projects! I had a question about [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Widgiemoolthalite&oldid=2003670 your edit] to the [[WikiJournal Preprints/Widgiemoolthalite|Widgiemoolthalite preprint]] at ''WJS''. I checked through the article's history and while it was imported from Wikipedia, I don't believe the [[WikiJournal_User_Group/Publishing#Acknowledgement_of_sources|>10% or 1 paragraph]] threshold for work contributed by other editors was met, which is why I left the link to the article's contributors in the Acknowledgements rather than as an ''et al.'' link. Was I correct in doing this? Thank you kindly! Best, [[User:Bobamnertiopsis|Bobamnertiopsis]] ([[User talk:Bobamnertiopsis|discuss]] • [[Special:Contributions/Bobamnertiopsis|contribs]]) 03:33, 7 May 2019 (UTC) :{{re|Bobamnertiopsis}} Aha, thank you. You are correct, I had not noticed the attribution section. Thank you for checking. Please feel to remove the {{para|et al}} parameter. You already correctly added the <code><nowiki>|license={{CC-BY-SA work}}</nowiki></code>, so that should all be fine! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:48, 7 May 2019 (UTC) ::Fabulous, thank you! [[User:Bobamnertiopsis|Bobamnertiopsis]] ([[User talk:Bobamnertiopsis|discuss]] • [[Special:Contributions/Bobamnertiopsis|contribs]]) 16:11, 7 May 2019 (UTC) Hi Evolution and evolvability, Is this review date "2015-12-31" correct for Robert Hazen's review? It appears to predate the article's existence on Wikipedia? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:44, 14 May 2019 (UTC) :{{re|Marshallsumter}} Thank you for notifying me. For some reason the date parameter was omitted so the template put in a default. I've updated the date, and edited the template so that it doesn't do something so misleading! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:29, 14 May 2019 (UTC) == Reviewer credentials == Hey Thomas, I got a question for you. While [https://en.wikiversity.org/w/index.php?title=Talk%3AWikiJournal_of_Science%2FA_card_game_for_Bell%27s_theorem_and_its_loopholes&type=revision&diff=2030070&oldid=2008763 entering the credentials] of the reviewer's institution, should we use the institution's native name or translated English name? That example is perfect as one is French and the other is German, yet both are easy to understand even if you don't know a single word in French or German. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 00:00, 9 July 2019 (UTC) ::{{re|OhanaUnited}} I'd go for the original language when in doubt to avoid any possibly ambiguity from alternative possible translations (unless it is more well known my its translation e.g. "Max Planck Institute of Biochemistry"). The priority is for it to be unambiguously identifiable, so even putting the translation with the original in brackets could work when it seems useful. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:22, 9 July 2019 (UTC) ==Paper== Thomas, I tried replying by email but it bounced saying unusual spamming from my IP! I copyedited the paper as requested; I hope not to have changed any meanings, so perhaps your expert eye would be beneficial for a final check. [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 12:45, 8 August 2019 (UTC) :{{re|Chiswick Chap}} Fantastic, thank you! I've had look through the new version and the diffs and it's a great improvement.I'll do an additional sweep through before confirming with the author that they're ok wth the edits. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 16:58, 8 August 2019 (UTC) == [[WikiJournal of Medicine/Medical gallery of Mikael Häggström 2014]] == I'm not quite sure how to troubleshoot the category error in question on this page. And I have not seen this kind of error before. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 15:12, 22 August 2019 (UTC) :{{re|OhanaUnited}} Very odd. I'll get on that - thanks for the note. It should just be placing it in [[:Category:Articles_submitted_for_peer_review_in_2014]] based on the {{para|submitted}} year. I'll dig into the {{tlx|Article info main}} code to find the error. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:23, 24 August 2019 (UTC) ::Super weird. there's some secret difference between the characters "2014‎" and "2014". I think some hidden zero-width space character? Should be fixed now anyway. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 14:11, 24 August 2019 (UTC) ::: It seems more common than I thought. Here's [[Talk:WikiJournal of Science/Baryonyx#Additional peer review on Wikipedia|another page]] with similar error. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 02:18, 26 August 2019 (UTC) ::::{{re|OhanaUnited}} Rats. The fix is to check if there's a zero-width space before or after the date and remove it. I'll go through to check some others. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:20, 26 August 2019 (UTC) ::::{{re|OhanaUnited}} I think I've found them all, so that should be fixed now. Thanks again for spotting the initial problems! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 05:28, 27 August 2019 (UTC) ::::: There's one more: [[Talk:WikiJournal of Medicine/Medical gallery of Blausen Medical 2014#Second peer review - intracranial electrodes]] [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 04:01, 1 September 2019 (UTC) == Community Insights Survey == <div class="plainlinks mw-content-ltr" lang="en" dir="ltr"> '''Share your experience in this survey''' Hi {{PAGENAME}}, The Wikimedia Foundation is asking for your feedback in a survey about your experience with {{SITENAME}} and Wikimedia. The purpose of this survey is to learn how well the Foundation is supporting your work on wiki and how we can change or improve things in the future. The opinions you share will directly affect the current and future work of the Wikimedia Foundation. Please take 15 to 25 minutes to '''[https://wikimedia.qualtrics.com/jfe/form/SV_0pSrrkJAKVRXPpj?Target=CI2019List(other,act5) give your feedback through this survey]'''. It is available in various languages. This survey is hosted by a third-party and [https://foundation.wikimedia.org/wiki/Community_Insights_2019_Survey_Privacy_Statement governed by this privacy statement] (in English). Find [[m:Community Insights/Frequent questions|more information about this project]]. [mailto:surveys@wikimedia.org Email us] if you have any questions, or if you don't want to receive future messages about taking this survey. Sincerely, </div> [[User:RMaung (WMF)|RMaung (WMF)]] 14:34, 9 September 2019 (UTC) <!-- Message sent by User:RMaung (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=CI2019List(other,act5)&oldid=19352874 --> == Reminder: Community Insights Survey == <div class="plainlinks mw-content-ltr" lang="en" dir="ltr"> '''Share your experience in this survey''' Hi {{PAGENAME}}, A couple of weeks ago, we invited you to take the Community Insights Survey. It is the Wikimedia Foundation’s annual survey of our global communities. We want to learn how well we support your work on wiki. We are 10% towards our goal for participation. If you have not already taken the survey, you can help us reach our goal! '''Your voice matters to us.''' Please take 15 to 25 minutes to '''[https://wikimedia.qualtrics.com/jfe/form/SV_0pSrrkJAKVRXPpj?Target=CI2019List(other,act5) give your feedback through this survey]'''. It is available in various languages. This survey is hosted by a third-party and [https://foundation.wikimedia.org/wiki/Community_Insights_2019_Survey_Privacy_Statement governed by this privacy statement] (in English). Find [[m:Community Insights/Frequent questions|more information about this project]]. [mailto:surveys@wikimedia.org Email us] if you have any questions, or if you don't want to receive future messages about taking this survey. Sincerely, </div> [[User:RMaung (WMF)|RMaung (WMF)]] 19:13, 20 September 2019 (UTC) <!-- Message sent by User:RMaung (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=CI2019List(other,act5)&oldid=19395141 --> == Reminder: Community Insights Survey == <div class="plainlinks mw-content-ltr" lang="en" dir="ltr"> '''Share your experience in this survey''' Hi {{PAGENAME}}, There are only a few weeks left to take the Community Insights Survey! We are 30% towards our goal for participation. If you have not already taken the survey, you can help us reach our goal! With this poll, the Wikimedia Foundation gathers feedback on how well we support your work on wiki. It only takes 15-25 minutes to complete, and it has a direct impact on the support we provide. Please take 15 to 25 minutes to '''[https://wikimedia.qualtrics.com/jfe/form/SV_0pSrrkJAKVRXPpj?Target=CI2019List(other,act5) give your feedback through this survey]'''. It is available in various languages. This survey is hosted by a third-party and [https://foundation.wikimedia.org/wiki/Community_Insights_2019_Survey_Privacy_Statement governed by this privacy statement] (in English). Find [[m:Community Insights/Frequent questions|more information about this project]]. [mailto:surveys@wikimedia.org Email us] if you have any questions, or if you don't want to receive future messages about taking this survey. Sincerely, </div> [[User:RMaung (WMF)|RMaung (WMF)]] 17:04, 4 October 2019 (UTC) <!-- Message sent by User:RMaung (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=CI2019List(other,act5)&oldid=19435548 --> == Radiocarbon dating == Hi Thomas. ''British Archaeology'', the journal of the [https://en.wikipedia.org/wiki/Council_for_British_Archaeology Council for British Archaeology], has a box in each issue recommending the Wikipedia article on radiocarbon dating for information on the subject. Last month, I wrote to the journal informing them of the WJS article and they have published my letter in the November/December 2019 issue and changed to recommending the WJS version. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|talk]]) 14:34, 10 October 2019 (UTC) :{{re|Dudley Miles}} Very interesting! Thank you for both contacting them and for your post here and on the wikipedia article's talkpage. It's an idea that might be cross-applicable to other journals and magazines on different topics. Would you be willing to send me the email text that you sent? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:29, 11 October 2019 (UTC) ::I have forwarded the email to you. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 08:25, 11 October 2019 (UTC) == started an article == heya I have started putting an article together [[user:Faendalimas/What_is_in_a_Name]], it is based on a plenary speech I gave at an international conference in 2018, many people have been asking me to publish it. So I am writing it out, would appreciate your thoughts. Cheers [[User:Faendalimas|<span style="color: #004730">Scott Thomson</span>]] (<small class="nickname">Faendalimas</small>) ^{[[User talk:Faendalimas|<span style="color: maroon">talk</span>]]} 00:50, 3 November 2019 (UTC) :{{re|Faendalimas}} In general, we've avoided opinion articles to prevent the risk of either a) the article can't really be peer reviewed or b) the journals look like just a blogging site which could undermine the other articles. However ''really'' the distinction is whether an article could be reasonably peer reviewed. I think if the article can be written as a case study and proposal then that probably can be put to reviewers as to whether e.g. the relevant background and related work is clearly described, the current issues are accurately put forward, the proposal addresses the issues raised and the case is convincingly made. It'd have to be put to the other board members since it is still different from anything previously published in the journals. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:19, 3 November 2019 (UTC) == Re: Maps via Wikidata == Very nice. I was wondering if it can be loaded directly when user visits a page (kind of like my current [[User:OhanaUnited/sandbox|sandbox]]). Another thing is if there's a way to manually specify the location. For instance, the map directly loads my employer's headquarter location (Ottawa) even though I'm in Toronto. And do you know why the map shows my profile twice in Ottawa? I couldn't quite figure it out. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 22:35, 23 November 2019 (UTC) :So I've asked over at [[Wikidata:Wikidata:Project_chat#Embedding_query_result_in_wikimedia_page]], but there was no obvious answer. Maybe there's some location to ask over at wikivoyage, where they probably have more experience with such things? Otherwise, on other pages I've just included a screenshot that links to the live query ([[metawiki:Wikimedian_in_residence|example]]). The way I'm c alculating location is to just use the listed location of the employer (easiest to see in the [https://w.wiki/Ccf table output of the same query]), but there might be a way to check whether a location is listed for the person themself. Your double listing on {{q|Q22674854}} was an error that I've now fixed. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:49, 24 November 2019 (UTC) == wikipediajournal.com == Hi. Would you be willing to make me an account on wikipediajournal.com? I'd like to try some of the extensions there, and see if I have any ideas for user scripts that'll help the project. Thanks, --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 09:36, 2 December 2019 (UTC) :{{re|DannyS712}} Thanks! I think that should be fine What sorts of extensions are you thinking? Pinging {{u|Bryandamon}} who set the test wiki up. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:27, 2 December 2019 (UTC) ::I was just going to test what is installed already --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 11:10, 2 December 2019 (UTC) :::{{Re|DannyS712}} Sounds excellent. I've asked bryan to add you (currently beyond my knowledge). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:35, 2 December 2019 (UTC) :::{{Re|DannyS712}} Should be done now. Let me know if it's not working and I'll follow-up. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:39, 2 December 2019 (UTC) ::::It worked, thanks --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 00:27, 3 December 2019 (UTC) == [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Abū_al-Faraj_al-Iṣfahānī&diff=next&oldid=2107575 This edit] == Hi. Please look at the above linked edit. I think you may have accidentally changed the words to be incorrect. [[User:Vermont|Vermont]] ([[User talk:Vermont|discuss]] • [[Special:Contributions/Vermont|contribs]]) 12:02, 17 December 2019 (UTC) == Italicizing title == I understand that [https://en.wikiversity.org/w/index.php?title=Template:Article_volume_summary&diff=2014069&oldid=2013542 you added italics parameter] to {{tl|Article volume summary}}. I think we need a different approach. If we set italics=yes in the template, the entire title is italicized, including parts that should not be italicized.[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Volume_4_Issue_1&diff=prev&oldid=2124525] If I use wiki markup directly in the title,[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Volume_2_Issue_1&diff=2124526&oldid=1716339] it breaks the link in the title and the full-text link. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 07:05, 22 February 2020 (UTC) :Have a look at [[WikiJournal Preprints/Abū al-Faraj ʿAlī b. al-Ḥusayn al-Iṣfahānī, the Author of the Kitāb al-Aghānī|this page]] which might have a solution. The code below should work on the page. I'll add a {{para|display_title}} parameter to the [[template:Article volume summary|relevant template]] that's used on the volume/issue page. <pre> {{DISPLAYTITLE:<span style="font-family:Century Gothic, Helvetica, sans serif; font-size: 10pt">{{BASEPAGENAME}}</span><span style="color:#DDD">/</span><span style="font-family:Century Gothic, Helvetica, sans serif;">Images of </span><span style="font-family:Century Gothic, Helvetica, sans serif;font-style:italic;">Aerococcus urinae</span>}} </pre> :[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:35, 22 February 2020 (UTC) == Template:Information and Wikidata == Something about the changes to [[Template:Information]] is incomplete. The three files you added are showing up in [[:Category:Files with no machine-readable author]], [[:Category:Files with no machine-readable description]], and [[:Category:Files with no machine-readable source]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 19:54, 23 May 2020 (UTC) :{{re|Dave Braunschweig}} Thanks! I've created a substitutable wrapper template {{tlx|InformationQ}} that seems to solve it! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:36, 24 May 2020 (UTC) == Adding a file in response to reviewer == Hi Thomas, could I ask you to have a quick check at [[Talk:WikiJournal Preprints/Beak and feather disease virus]]? The authors have made updates to the article based on the reviewer comments, and also provided a change-tracked document of these. I couldn't figure out an elegant method to attach that - the {{tl|response}} template does not take a file argument. So I stuck it in as an image thumbnail, which is probably less than ideal. I suspect there's a better method? Cheers --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 16:00, 13 June 2020 (UTC) :{{re|Elmidae}} No problem - I've added a {{para|pdf}} parameter to the {{tl|response}} template, so that it can be added. Good point that it was a missing capability. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:51, 14 June 2020 (UTC) ::Ah, most well crafted :) Thanks. --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 20:20, 14 June 2020 (UTC) ==Congrats!== *[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Applications/SCOPUS&diff=2171184&oldid=2125794 very well done]--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:43, 19 June 2020 (UTC) == Æthelfæd == Hi Thomas. An editor has deleted an edit at [https://en.wikipedia.org/w/index.php?title=%C3%86thelfl%C3%A6d&diff=next&oldid=971886775] which I assume you made. I will leave you to deal with it if you wish as I do not know the rules on this. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 16:04, 12 August 2020 (UTC) :{{re|Dudley Miles}} Aha, rats. Thank you for letting me know. I've also just been alerted to a related conversation all about it [[wikipedia:Wikipedia_talk:WikiProject_Medicine#Improper_use_of_template%2C_diverting_en.Wikipedia_readership|here]], so will have a read through that now and respond. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:03, 13 August 2020 (UTC) == [[:WikiJournal_of_Medicine/Alternative_layout2]] == As you seem to be responsible for a number of templates on which this depends , perhaps you can determine why this misrenders? Also why {{tl|Article info}} misrenders, generating unclosed DIV sequences... Thanks.. [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 18:20, 18 August 2020 (UTC) : There seem to be a lot of LintErrors generated despite attempts by me to fix the problem (as yet unsuccessfully). : https://en.wikiversity.org/w/index.php?title=Special:LintErrors/missing-end-tag&dir=prev&offset=482875 [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 18:22, 18 August 2020 (UTC) == You've got mail == {{You've got mail}}'''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 19:32, 22 September 2020 (UTC) == ... == Well, that wasn't all that helpful, was it :/ Sorry, wasn't aware that there was an actual "response" template. Will keep it in mind for next time! Cheers --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 14:42, 10 October 2020 (UTC) :And now I realize that we talked about that very template before, on this very page, and I still didn't remember! I need a holiday... --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 18:32, 11 October 2020 (UTC) == Testing out new reply to tool on my talkpage == Comment *list *list *list Comment [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:58, 15 October 2020 (UTC) :test reply [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:59, 15 October 2020 (UTC) ::Hi Thomas, it works ... PS it's under "Beta features" on people's Preferences page. Ian [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 08:42, 15 October 2020 (UTC) :::Works in Firefox on windows. [[User:J S Lundeen|J S Lundeen]] ([[User talk:J S Lundeen|discuss]] • [[Special:Contributions/J S Lundeen|contribs]]) 13:44, 15 October 2020 (UTC) == Update submitted article == We would like to rework the submitted article https://en.wikiversity.org/wiki/WikiJournal_Preprints/Androgen_backdoor_pathway Can you please point to correct path to sandbox and then resubmit? Or we may edit it now until (before) we get peer reviewers assigned? We would like to make substantial edits. ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 18:48, 26 October 2020 (UTC) :{{re|Maxim Masiutin}} Since we have not yet contacted the peer reviewers, you have two options: :#ask us to wat before contacting reviewers and update the article directly :#create a copy at https://en.wikiversity.org/wiki/WikiJournal_Preprints/Androgen_backdoor_pathway/sandbox that you can continue editing whilst reviewers comment :let me know what you prefer [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:18, 26 October 2020 (UTC) ::{{re|Evolution and evolvability}} Thank you, I have created the sandbox page at the URL that you have provided, so we can continue editing whilst reviewers comment ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 09:47, 27 October 2020 (UTC) :::{{re|Maxim Masiutin}} Ok, and thanks for adding the link to the tracking table. To confirm, the peer reviewers will be asked to review the main article page and not the /sandbox. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:44, 28 October 2020 (UTC) ::::{{re|Evolution and evolvability}} Thank you, I understand that the peer reviewers will be asked to review the main article page and not the /sandbox. ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 16:25, 28 October 2020 (UTC) == Self-closed tags == There's a recent error in one or more WikiJournal templates that is generating 350+ lint errors. See [[Special:LintErrors/self-closed-tag]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 01:55, 7 November 2020 (UTC) :@[[User:Dave Braunschweig|Dave Braunschweig]]: Aha, sorry about that. I've tracked the bug and fixed it! Was using a bit of html that I don't really understand to auto-number figures using [[template:WikiJournal/figure/styles.css]]. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 08:14, 7 November 2020 (UTC) ==COVID-19== Dr Shafee, may submit by April (depending on vaccine[https://xtools.wmflabs.org/authorship/en.wikipedia.org/COVID-19%20pandemic/])--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 14:30, 15 November 2020 (UTC) == Suggested citation format == Hello, hope you are doing well. There's a problem on all "Suggested citation format", for example see [[WikiJournal of Medicine/Viewer interaction with YouTube videos about hysterectomy recovery]]. Best '''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 00:34, 29 November 2020 (UTC) :{{re|علاء }} Thanks for spotting that! Now fixed. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:51, 29 November 2020 (UTC) ::Thanks! '''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 12:18, 29 November 2020 (UTC) == Steps in [[WikiJournal of Science/Potential upcoming articles]] == Are the steps/legends still applicable now that the table is auto-populated based on Wikidata and no longer shows which stage an article is at? [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 16:26, 30 November 2020 (UTC) :{{re|OhanaUnited}} Good point. We probably still need to indicate the the general order of events, but that might be better as a schematic picture? Something like a process diagram, or a more focused, horizontal version of [[:File:WikiJournal of Science publishing pipeline (wiki first).svg|this]]. The one thing I've not worked out how to usefully automate via wikidata is when each review has been responded to, which would be needed to differentiate what was called '4,5,6'. [[metawiki:WikiJournal_User_Group/Meetings/2019-12-18|Integration with OJS]] could solve that, so it's back up the priority list for next year! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:40, 1 December 2020 (UTC) :: I think, in the interest of openness, we can mention which stage it is on under the "Notes" section. Or maybe add one column to the table to describe which it is at (without the Wikidata linkage). [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 06:27, 4 December 2020 (UTC) == et al. == According to [[Wikipedia:Category:CS1 errors: explicit use of et al.]], "et al." is no longer a valid author name. Instead, we are supposed to use <code>|display-authors=etal</code>. I'm not sure how this can be resolved using Wikidata entries, but it does need to be addressed at some point. See our own [[:Category:CS1 errors: explicit use of et al.]] for affected resources. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:32, 1 December 2020 (UTC) :{{re|Dave Braunschweig}} Yes, there was also some conversation about it over at [[wikipedia:Template_talk:Citation#Et_al|this page]]. Currently I've made a workaround in {{tlx|Cite Q EtAl}} by including a hyperlinked 'et al.' which the software doesn't recognise (a temporary cheat), but ove the cite_Q template has stabilised (still lots of changes occurring) It should be possible to implement a <code>|display-authors=etal</code>-based solution. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:47, 1 December 2020 (UTC) == License == [[:File:What are Systematic Reviews.pdf]] has copyright information but is missing a license. See [[:Category:Files with no machine-readable license]]. Perhaps you can add a License or Permission value that would include the license. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:43, 1 December 2020 (UTC) :{{re|Dave Braunschweig}} Thanks for catching that. Fixed (both via updating wikidata, and by adding the relevant template below)! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:30, 1 December 2020 (UTC) == Paper status == Hi T.Shafee, My [[WikiJournal_Preprints/Affine_symmetric_group|submission]] to WJS has been sitting around for more than six months with no visible progress on refereeing. I e-mailed the assigned editor a week ago to inquire about the status of the refereeing process, but I have not received a response. I was hoping you could look into the matter. Thanks, [[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 21:34, 30 January 2021 (UTC) :{{re|JayBeeEll}} Thanks for letting me know. I'll look into it and organise a change in editor if the current editor isn't available any more. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 05:58, 31 January 2021 (UTC) :: Thank you, I appreciate it. --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 13:01, 31 January 2021 (UTC) :::{{re|JayBeeEll}} The final review is now in for the article ([[Talk:WikiJournal_Preprints/Affine_symmetric_group#Peer_review_3|link]]). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:06, 26 February 2021 (UTC) :::: Thanks! --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 00:31, 26 February 2021 (UTC) :::: I did not find a button to push to indicate that I have completed my response to the referees (and accompanying article edits); I hope that leaving this comment here is an accepted method! --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 20:17, 18 March 2021 (UTC) :::::{{re|JayBeeEll}} Excellent, thank you. I'll notify any reviewers that asked to see the article again, and if they have no additional items, the board will vote in the coming weeks! We're hoping to make an easier to use back-end for making sure that authors, reviewers and editors can easily update an article's stage and be notified when they have the ball back in their court, but in the meantime, you're right that this not is as good a place as any! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:35, 19 March 2021 (UTC) == [[:Template:Fig]] == Please check your logic, It's leaking a DIV in certain instances. such as in [[WikiJournal_of_Science/About]] [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 13:43, 7 February 2021 (UTC) : {{ping|Evolution and evolvability}} Did you actually want something more like the code in [[User:ShakespeareFan00/sandbox|my sandbox]] where the possibility of a 'nil' or absent 1st paramater is considered? [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 16:06, 10 February 2021 (UTC) ::{{re|ShakespeareFan00}} Thank you so much for your testing on this. I appreciate that the complexity of the structure makes it frustrating! I've been using [[Template:Fig/sandbox|this page]] as a test page. And your sandbox solution seems to make sense. I'd thought the leaky div was something to do with the guess it must be something to do with the <code><nowiki><dl class="figure-n-counter-set-to-zero"></dl></nowiki></code>. It had seemed to work fine for images inserted in the default <code><nowiki>[[File.example.jpg|thumb|caption]]</nowiki></code> format, so I also tried to implement it into the <code><nowiki>{{fig|...}}</nowiki></code> (which can act as a multiple image holding template) for when a page is going to contain a mixture of <code><nowiki>[[file:...]]</nowiki></code> and <code><nowiki>{{fig|...}}</nowiki></code>. It seems your solution does what I was thinking without leaking the div though. Thanks again for looking into it. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:57, 10 February 2021 (UTC) == Stage-scripts.. == Over on English Wikisource I wrote some templates for formatting 'drama' scripts. Would it be possible to get an import of the Stagescript template family over here on Wikiversity? The reason is that I wanted to do a reformat on some material I wrote a while back. https://en.wikisource.org/wiki/Special:AllPages?from=Stagescript&to=&namespace=10 It's the templates at the top of the list. The way I wrote the template and styles, it should be straightforward to adapt for various script/screenplay formats, by writing appropriate style-sheets? [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 01:46, 4 March 2021 (UTC) :{{re|ShakespeareFan00}} That should be fine! I've imported those across now, so let me know if they look like they're working. Nice organisation of the template set. I would suggest also making a [[Template:Stagescript]] page as the main documentation page just so that there's a root page when people look. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:35, 4 March 2021 (UTC) ::If you want to start documenting feel free. Whilst my format isn't exactly the same as a production format, I've based some aspects of the model on the examples here ( essentially the screenplay and US Radio Drama formats)- https://www.bbc.co.uk/writersroom/resources/medium-and-format. If you know CSS , you can add formats closer to those examples. Also I am wondering if for Wikisource purposes we need a /slide template in addition to /sdr1 and /fx. The template fammily can then be used to develop 'presentational' scripts, as well as drama. [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 12:08, 5 March 2021 (UTC) == A Barnstar for you! == {{The Shootin Barnstar|color=Black|textcolor=I can see you are already doing well here. Keep going and happy editing. --[[User:IamTheAstronomer|IamTheAstronomer]] ([[User talk:IamTheAstronomer|discuss]] • [[Special:Contributions/IamTheAstronomer|contribs]]) 23:43, 21 March 2021 (UTC)}} == You have earned the Wikiversitian Award! == [[File:Wikiversity-logo.svg|thumb|left|124px]] May I present the Wikiversitian Award to this editor due to the fact that they have been an exceedingly outstanding contributor here. Believing they are an editor who has a huge level of competence, I decided to present this award to them for making Wikiversity the community it is meant to be. I wish this editor good luck with all their future endeavours. --[[User:IamTheAstronomer|IamTheAstronomer]] [[User talk:IamTheAstronomer|Talk]] 20:50, 30 March 2021 (UTC) == Copying links == Hi Thomas. Thanks for your help. I have copied the Wikipedia article to [[User:Dudley Miles/sandbox]] to work on it. I could easily create wikilinks by changing [[ to [[w:, but that leaves links as e.g. <nowiki>[[w:Mercia]]</nowiki>. Do I have to manually change every link to <nowiki>[[w:Mercia|Mercia]]</nowiki> or is there a way to automate this? [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 12:49, 27 September 2021 (UTC) :@[[User:Dudley Miles|Dudley Miles]]: Yes, you can change all the links in the page to point to wikipedia using: :* at the top of the section or page: <code><nowiki>{{subst:</nowiki>[[Template:Convert links|convert_links]]|</code> :* at the bottom of the section or page: <code><nowiki>}}</nowiki></code> :I've gone ahead and done so in your sandbox (after removing the <code>w:</code>currently present), so hopefully that worked, but let me know if any didn't link up correctly. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:04, 28 September 2021 (UTC) ::Many thanks for your help Thomas. ::Am I correct in thinking that [[Template:Sfn]] only partly implements [[w:Template:Sfn]]? In Wikipedia hovering over the reference number in the text gives you an option to go straight to the source, including opening a web page, but in Wikiversity I only seem to be able to go to the citation and then manually find the source. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 09:00, 28 September 2021 (UTC) :::@[[User:Dudley Miles|Dudley Miles]]: Hmm, check your [[Special:Preferences#mw-prefsection-gadgets|preferences]]. I think it's the '[[mw:Reference_Tooltips|reference tooltips]]' gadget that's enabled by default on WP but still available on WV. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:05, 29 September 2021 (UTC) I have been working out how to manage editing in Wikiversity. I cannot get tooltips to work in my sandbox on either of my computers. However, I am not sure what is going on as it seems to work on my mobile phone and works for my computers on preprints. I have also been bodging to get sfn working. It does not work correctly in Wikiversity with the cite encyclopedia template. I also find I need to use the harvid field in the sources for it to work correctly. In fact, it then works better than on Wikipedia. The great advantage of sfn used to be that it highlights reference errors and unused sources, but the latter function was removed on Wikipedia. Both functions still work on Wikiversity. Thanks. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 14:00, 29 September 2021 (UTC) == How we will see unregistered users == <section begin=content/> Hi! You get this message because you are an admin on a Wikimedia wiki. When someone edits a Wikimedia wiki without being logged in today, we show their IP address. As you may already know, we will not be able to do this in the future. This is a decision by the Wikimedia Foundation Legal department, because norms and regulations for privacy online have changed. Instead of the IP we will show a masked identity. You as an admin '''will still be able to access the IP'''. There will also be a new user right for those who need to see the full IPs of unregistered users to fight vandalism, harassment and spam without being admins. Patrollers will also see part of the IP even without this user right. We are also working on [[m:IP Editing: Privacy Enhancement and Abuse Mitigation/Improving tools|better tools]] to help. If you have not seen it before, you can [[m:IP Editing: Privacy Enhancement and Abuse Mitigation|read more on Meta]]. If you want to make sure you don’t miss technical changes on the Wikimedia wikis, you can [[m:Global message delivery/Targets/Tech ambassadors|subscribe]] to [[m:Tech/News|the weekly technical newsletter]]. We have [[m:IP Editing: Privacy Enhancement and Abuse Mitigation#IP Masking Implementation Approaches (FAQ)|two suggested ways]] this identity could work. '''We would appreciate your feedback''' on which way you think would work best for you and your wiki, now and in the future. You can [[m:Talk:IP Editing: Privacy Enhancement and Abuse Mitigation|let us know on the talk page]]. You can write in your language. The suggestions were posted in October and we will decide after 17 January. Thank you. /[[m:User:Johan (WMF)|Johan (WMF)]]<section end=content/> 18:14, 4 January 2022 (UTC) <!-- Message sent by User:Johan (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=User:Johan_(WMF)/Target_lists/Admins2022(3)&oldid=22532499 --> ==question== Dr. Shafee I realize your busy, however I was wondering what the timetable might be for PDF [https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/The_Kivu_Ebola_Epidemic] its been about 1 month and a half since 13 April (I of course, know there are several articles you deal with from WikiJournal). I want to thank you for your very valuable time as always, Ozzie--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:05, 4 June 2022 (UTC) :@[[User:Ozzie10aaaa|Ozzie10aaaa]]: Thanks for flagging, and apologies for the delay. I'm in the process of training new users on how to do the off-wiki PDF formatting, so will use it as an example (as you've noticed, we have a bit of a backlog!). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 04:20, 12 June 2022 (UTC) ::Dr Shafee, I completely understand and thank you as always, Ozzie--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:28, 12 June 2022 (UTC) == Files Missing Information == Thanks for uploading files to Wikiversity. All files must have source and license information to stay at Wikiversity. The following files are missing {{tlx|Information}} and/or [[Wikiversity:License tags]], and will be deleted if the missing information is not added. See [[Wikiversity:Uploading files]] for more information. {{colbegin|3}} * [[:File:Ziats Table1.png]] * [[:File:Ziats)Figure 1.jpg]] {{colend}} [[User:MaintenanceBot|MaintenanceBot]] ([[User talk:MaintenanceBot|discuss]] • [[Special:Contributions/MaintenanceBot|contribs]]) 02:00, 23 June 2022 (UTC) == A number of backlogged WJS submissions == Hi Thomas, there are a few WJS submissions which listed you as the peer review coordinator. I was wondering what the status are for those submissions: # [[WikiJournal Preprints/Induced stem cells]] (no records of having peer reviews submitted) # [[WikiJournal Preprints/Moisture Content as a Proximate Factor in Nest Site Attractiveness for Temnothorax rugatulus]] (I will follow up with the author as he appears to be somewhat active on Wikipedia) # [[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] (authors need to respond to third reviewers' second-round of comments; pinging {{u|Kaexer}} to transclude [[Talk:WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats#Updated manuscript|updated PDF manuscript]] and {{u|Agan56}} to get ready for correspondence with this reviewer) If you have additional information for any of these submissions, please let me know. Thanks. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:52, 10 July 2022 (UTC) == File name error == Hi Thomas, one of the tech editor accidentally thought the authors' version was the accepted version and uploaded the file with that article's name with that assumption. Can you delete [[:File:Perspectives on the social license of the forest products.pdf]] since I can't rename/move the file to another name? [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 16:02, 15 July 2022 (UTC) :No problem. I've moved it to [[:File:Perspectives on the social license of the forest products - Author's response.pdf|File:Perspectives on the social license of the forest products - Author's response.pdf]] and deleted the redirect page left behind. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:07, 18 July 2022 (UTC) ::Thanks very much. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:36, 18 July 2022 (UTC) == Continuing Email Discussion == Hello T. Shafee, I've sent you an email back in March regarding the [[WikiJournal Preprints/The Effect of Corticosteroids on the Mortality Rate in COVID-19 Patients, v2]] medical paper. I'm assuming you might've missed it, which isn't an issue! I can ask the questions here: * I wanted to get a confirmation that the topic is suitable for a medical paper. I see that there are similar studies on the internet in regards to this as recent as December 2021--just wanted to make sure my efforts are being put into a useful field. * Is it an obligation to mention the number of studies incorporated in the medical paper? Thank you! —[[User:Atcovi|Atcovi]] [[User talk:Atcovi|(Talk]] - [[Special:Contributions/Atcovi|Contribs)]] 21:21, 20 July 2022 (UTC) 64lb87i2zsl9tj6dd2p1towkdve5vpc 2408227 2408226 2022-07-20T21:22:54Z Atcovi 276019 /* Continuing Email Discussion */ EDIT wikitext text/x-wiki === [https://en.wikipedia.org/wiki/User_talk:Evolution_and_evolvability My main Wikipedia usertalk page is here] === == Eukaryotic and prokaryotic gene structure == Hi Evolution and evolvability! [[WikiJournal of Medicine/Eukaryotic and prokaryotic gene structure|Eukaryotic and prokaryotic gene structure]] has been apparently completed as of 20 January 2017 and published in the [[WikiJournal of Medicine]]! Would you like this announced on our Main Page News? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 20:23, 21 January 2017 (UTC) :{{re|Marshallsumter}} That would be fantastic! Is there anything that I would need to do to facilitate that? <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:32, 22 January 2017 (UTC) == Template:Article info == There is an error in [[Template:Article info]] demonstrated on [[WikiJournal of Medicine/Diagram of the pathways of human steroidogenesis]] and [[Talk:WikiJournal of Medicine/Diagram of the pathways of human steroidogenesis]], where "expansion depth is exceeded. The error is specifically related to the <code>|accepted = 27 March 2014</code> parameter. If that line is removed, the error goes away. Please investigate. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 04:09, 12 February 2017 (UTC) ::Thanks {{u|Dave Braunschweig}}. I'll look into what's going on. It's evidently calling too many templates within templates. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 06:47, 12 February 2017 (UTC) == Template:Fig == There's an issue in [[Template:Fig]] with too many closing curly braces in a <nowiki>[[File:]]</nowiki> tag somewhere. I can't find it, though. See [[Special:LintErrors/bogus-image-options]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 00:26, 26 April 2017 (UTC) :Thank you! I'll see if I can find it. A quick search indicates that there are 886 opening and closing braces, so at least there's a matched number! I'll see if I can find an example where the template misformats, which might give a clue as to where the braces have been misplaced. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 00:43, 26 April 2017 (UTC) ::It's also possible that there's a bug in the reporting tool. There may be so many curly braces there that it got lost / confused. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:15, 27 April 2017 (UTC) :::See [https://en.wikiversity.org/w/index.php?title=Template%3AFig&type=revision&diff=1716029&oldid=1668697]. Alt needs to be conditional, and use {{tl|!}} to include the separator only when present. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 20:49, 4 August 2017 (UTC) ::::{{re|Dave Braunschweig}} Thank you! Sadly, one problem remains. The {{tl|!}} expands to a space in stead of a pipe when transcluded into a table (including in multicolumns layout. This is a problem because the multiple column layouts (like {{tl|col-begin}}) are useful for making columns that reflow into a single column on mobiles. See below for what I mean (note the link destinations): <pre>{{fig|1|Sobo 1909 639.png|capn|size=100px|link=main}}</pre> '''Correct transclusion:''' {{fig|1|Sobo 1909 639.png|capn|size=100px|link=main}} {{-}} '''Error when transcluded in table:''' {| | {{fig|1|Sobo 1909 639.png|capn|size=100px|{{!}}link=main}} |} {{clear}} You can force the separation in a table. See above. Also, I've been working on a better columns template. It's not fully tested yet, but try {{tl|Columns}}. It's better for mobile column display. We need to start moving away from tables for layout. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 17:33, 5 August 2017 (UTC) ::{{re|Dave Braunschweig}} Champion, thank you! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:15, 6 August 2017 (UTC) == Files Missing Information == Thanks for uploading files to Wikiversity. All files must have source and license information to stay at Wikiversity. The following files are missing {{tlx|Information}} and/or [[Wikiversity:License tags]], and will be deleted if the missing information is not added. See [[Wikiversity:Uploading files]] for more information. * [[:File:Vitamin D as an adjunct for acute community-acquired pneumonia among infants and children systematic review and meta-analysis.pdf]] [[User:MaintenanceBot|MaintenanceBot]] ([[User talk:MaintenanceBot|discuss]] • [[Special:Contributions/MaintenanceBot|contribs]]) 00:42, 30 June 2017 (UTC) :I added {{tl|Cc-by-sa-3.0}}. If that is incorrect, please update. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 00:45, 30 June 2017 (UTC) ::Thanks! Have edited to CC-BY-4. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 01:00, 30 June 2017 (UTC) == Curator Status == Would you have any interest in [[Wikiversity:Curators]] status? I'd be happy to nominate you. It provides extra tools that can make some of the editing you do easier. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:04, 14 October 2017 (UTC) :{{re|Dave Braunschweig}} Thank you for your suggestion. I'll read up more on that. It seems that many of those tools would be very useful. My only hesitation is that I've only contributed to a very specific corner of Wikiversity! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 01:35, 15 October 2017 (UTC) ::{{re|Dave Braunschweig}} I've now lodged my [[Wikiversity:Candidates for Custodianship#Evolution and evolvability .28talk .7C email .7C contribs .7C stats.29|application]] for Probationary Custodianship. If you'd consider being my mentor in this, I'd greatly appreciate your technical expertise and wiki experience. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 10:52, 25 October 2017 (UTC) :::Done. Please monitor the page for questions and discussion. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:55, 25 October 2017 (UTC) You are now a curator. Congratulations! Please visit [[Wikiversity:Support staff]] and add yourself to the list. Then visit [[Special:SpecialPages]] and individual page menus and check out the new tools. Let me know whenever you have questions. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 14:46, 30 October 2017 (UTC) :{{re|Dave Braunschweig}} Thank you for your original recommendation to apply, and for the subsequent support. It's good to be aboard. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 23:54, 30 October 2017 (UTC) == Editor in chief == Hi Thomas! I recently took on a new full-time job that is leaving me little time for wikis. I was trusting that sooner or later I would find the time and energy to catch up with all the changes going on in the WJS, but truth is I'm not seeing that moment coming any time soon. Therefore, I'd like to offer you the title of "editor in chief". I also considered [[User:Marshallsumter]], but although he's been the most active reviewer, you've been the most active editor, so I think that you're the most appropriate person for "editor in chief". Let me know if you want to take on this responsibility, and I'll be happy to update the board accordingly. Kind regards, --[[User:Sophivorus|Felipe]] ([[User talk:Sophivorus|discuss]] • [[Special:Contributions/Sophivorus|contribs]]) 00:54, 26 October 2017 (UTC) :@{{u|Sophivorus|Felipe}}: Thank you for your message. I Would be very happy to be Editor in Chief. Once the journal gets going and bylaws have been ratified we can hold a formal vote for Eic and assistant EiC roles. I hope that you'll stay involved, even if you can't devote the time you used to. Similarly, reaching out to potential contributors may be an effective 'time investment' if you happen to know people who might be interested in being involved. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 02:12, 27 October 2017 (UTC) ::Thanks for relieving me {{u|Evolution and evolvability|Thomas}}, I just updated the board. I'll definitely stick around and contribute when I can. Cheers! --[[User:Sophivorus|Felipe]] ([[User talk:Sophivorus|discuss]] • [[Special:Contributions/Sophivorus|contribs]]) 03:16, 28 October 2017 (UTC) == Current reviews == Hi Evolution and evolvability! As editor-in-chief, please feel free to review my reviews and make what ever changes or contacts you believe are necessary or appropriate to move a submission to acceptance! Also, I believe WikiJournal of Science could allow submission of original research as well. What do you think? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:42, 28 October 2017 (UTC) ::{{re|Marshallsumter}} Thanks for your great work on those! Could I check if there were any other reviewers for [[Dialectic_algorithm]] or [[Space_(mathematics)]]? If there's only one, would you mind contacting as few other people to ask them to be an external reviewer ([https://drive.google.com/file/d/0B4LQzkvkbO9YWmZjc0NvLU14Z2c/view?usp=sharing here's an example email template])? A good way is to look at the contact addresses for corresponding authors on cited papersm and/or ask the author for suggestions. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 05:53, 29 October 2017 (UTC) :::{{re|Evolution and evolvability}} "Could I check if there were any other reviewers for [[Dialectic algorithm]]?" Of course! Depending on your point of view, if you check out the [[Talk:Dialectic algorithm|discuss]] page, you'll read constructive reviewing by [[User:Koavf|Justin (<span style="color:grey">ko'''a'''vf</span>)]]<span style="color:red">❤[[User talk:Koavf|T]]☮[[Special:Contributions/Koavf|C]]☺[[Special:Emailuser/Koavf|M]]☯</span> prior to submission to WikiJournal of Science. This user may also be willing to add an additional review if you ask or believe more is needed. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 03:33, 30 October 2017 (UTC) :::{{re|Evolution and evolvability}} "Could I check if there were any other reviewers for [[Space_(mathematics)]]?" The Wikipedia version has been reviewed on [[w:Talk:Space (mathematics)]] also prior to submission. The expanded version per my review is here. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 03:48, 30 October 2017 (UTC). ::::{{re|Marshallsumter}} Excellent work, thanks. In order to be thorough I've also contacted a set of external academics to review them. I've used authors who have published in the relevant field (G-scholar search) and authors of references in: [[w:Logic_and_dialectic]], [[w:Argumentation_framework]], [[w:Argumentation_theory]] and [[w:Logic_of_argumentation]], as well as the various categories of [[w:Space_(mathematics)#Types_of_spaces]]. I've emailed you the list so that you have them on file. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 13:07, 30 October 2017 (UTC) ==Journal== I did an edit to the page about the journal related to humanities that you created. You stated that review would be done by medical experts. I inserted 'recognized' rather than medical. Best Regards, [[User:Barbara (WVS)|Barbara (WVS)]] ([[User talk:Barbara (WVS)|discuss]] • [[Special:Contributions/Barbara (WVS)|contribs]]) 13:57, 30 October 2017 (UTC) :{{re|Barbara (WVS)}} Thank you for picking up the oversight! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 23:36, 30 October 2017 (UTC) ::Not a problem. [[User:Barbara (WVS)|Barbara (WVS)]] ([[User talk:Barbara (WVS)|discuss]] • [[Special:Contributions/Barbara (WVS)|contribs]]) 18:17, 7 November 2017 (UTC) == "Article info" template == As far as I understand, nearly all the talk page to a submission is now just one parameter "review" to this template; and probably this is why we cannot edit sections (such as "Second review" or "Editorial comment") separately; a bit inconvenient. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 07:44, 4 November 2017 (UTC) ::You're right. It's an artefact of the way I first built the template. It should be solvable so I'll put some time into fixing it tomorrow. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:05, 4 November 2017 (UTC) ::::{{re|Tsirel}} Thanks for bringing this to my attention. I think I've addressed the issue now, but please let me know if you notice any strange behaviours or errors! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:02, 7 November 2017 (UTC) == The goal of WikiJournals == It seems, I misunderstood the goal of this movement. I believed that, born on Wikiversity, it intends to create learning resources. But now I see that it intends rather to create encyclopedic articles (and put them on Wikipedia). Hmmm... Wikipedia is already successful; Wikiversity is not. I rather wait for something like that but Wikiversity integrated. Sorry. Really, I do not understand, who needs peer reviewing for creating collections of excerpts from already existing reliable sources. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 12:01, 8 November 2017 (UTC) :: {{re|Tsirel}} Hi, I completely sympathise with the confusion. The whole concept of WikiJournals is still finding its feet. There are articles that have been published focused primarily on providing wikiversity teaching resources ([[WikiJournal of Medicine/Acute gastrointestinal bleeding from a chronic cause: a teaching case report|example]]), and some that are published as basically stand alone papers that don't yet integrate into any wikimedia project at all ([[WikiJournal of Medicine/Vitamin D as an adjunct for acute community-acquired pneumonia among infants and children: systematic review and meta-analysis|example]]). However, I think that there is a useful place for peer review of encyclopedic articles ([[WikiJournal of Medicine/The Hippocampus|example]]). Like writing an [[w:Review article|academic review article]], even summarised information can benefit from having independent experts. For example: ::# It ensures that the article is up to date and hasn't missed developments in the field ::# Non-wikipedian experts can be engaged as external peer reviewers, when they otherwise would have never contributed to wikimedia content ::# It gives readers a stable version of record to check that has an additional level of authoritativeness ::Wikipedia still suffers from a lack of credibility and this form of academic peer review is one way of improving it. I think that the space in mathematics article is ideal for re-integrating into Wikipedia as well as being a standalone teaching item. If you would like to also create more wikiversity-focused content, you could also create a second, textbook/course-material version for teaching the topic in a more step-by-step manner. Indeed, the journal would be be compatible with additional versions targeted at specific audiences, e.g.: ::* "Introduction to spaces in mathematics" - similar to [[w:Introduction to viruses|Introduction to viruses]] on wikipedia ::* "Spaces in mathematics (in simple english)" - similar to [https://simple.wikipedia.org/wiki/Virus Virus] in simple-english wikipedia ::* "Spaces in mathematics (for secondary school students)" ::I'll attempt clarify a bit better tomorrow! <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 12:56, 8 November 2017 (UTC) :::Thank you for the clarification. I am glad to know that different kinds of articles are allowed in WikiJournals (at least, for now). :::Yes, I see: the problem of credibility (of scientific Wikipedia articles) can be alleviated by WikiJournal articles included into Wikipedia. :::However, the problem of [[w:User talk:Jimbo_Wales/Archive_224#Science and math articles|inaccessibility]] (of scientific Wikipedia articles) needs another approach (I think so). It cannot be solved inside Wikipedia. But it could be solved (well, alleviated) by ''attaching'' explanatory articles, published in WikiJournals, to Wikipedia. I mean, not including them into Wikipedia, but linking them from relevant Wikipedia articles. :::This option is rarely used, but here is a recent example: the Wikipedia article "[[w:Representation theory of the Lorentz group]]" contains (in the end of the lead, and again in Sect. 3.2 "Technical introduction to finite-dimensional representation theory") a link to Wikiversity article "[[Representation theory of the Lorentz group]]". The reason is mostly "the blue link hell" problem, see [[w:Talk:Representation theory of the Lorentz group|arguments]] of [[w:User:YohanN7|the most active contributor]] there. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 18:21, 9 November 2017 (UTC) ::::{{re|Tsirel}} You make a good point that Wikipedia typically has a single article on a topic that is ''supposed'' to cater to all audiences simultaneously. In reality this is extremely difficult, and articles often tent towards begin highly technical (as the discussions you linked to described well). The "[[w:Introduction to viruses|introduction to]]" or "[https://simple.wikipedia.org/wiki/Virus simple English]" articles are one possible solution. Another solution that I've seen is to have a non-technical summary section (e.g. in the [[wikipedia:Higgs_boson#Non-technical_summary|Higgs Boson]]). Your idea of also having attached explanatory notes is a also good one, and could be done in WikiJournals in a step-by-step textbook style article. <span class="nowrap">[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]}</span> 03:09, 25 November 2017 (UTC) :::::"Introduction to" idea was discussed on [[w:WT:WPM]] several times, and rejected as content forking that can be tolerated only as a rare exception (namely, only for Intro to General relativity and Intro to Quantum mechanics). :::::"Simple English"? Hmmm... I do not know what is considered "simple English", but I doubt that it can be something like <small>"Every point of the affine space is its intersection with a one-dimensional linear subspace (line through the origin) of the (n+1)-dimensional linear space. However, some one-dimensional subspaces are parallel to the affine space; in some sense, they intersect it at infinity."</small> or <small>"Away from the origin, the quotient by the group action identifies finite sets of equally spaced points on a circle. But at the origin, the circle consists of only a single point, the origin itself, and the group action fixes this point."</small> Or can it? :::::"Non-technical summary section"? Probably it may contain something like <small>"The type of space that underlies most modern algebraic geometry was introduced by Alexander Grothendieck and is called a scheme. One of the building blocks of a scheme is a topological space."</small> but hardly these not-so-simle-English phrases above. :::::Also, look (again) at my [[w:Conditioning (probability)]]. It is an explanatory essay, but it consists mostly of formulas. Surely not a simple English, nor a non-technical summary. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 11:04, 25 November 2017 (UTC) :::::Another well-known hard problem with math on WP is, examples. It is impossible to explain mathematics without many examples. But on WP an example is, almost inevitably, either Original Research, or Copyright Violation (since only rarely a single example appears in many textbooks). [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 11:46, 25 November 2017 (UTC) {{od}} {{re|Tsirel}} Very good points. I think for the [[Spaces in mathematics|Spaces in Mathematics]] article, the decider for its final style and format is your preferences for whether you want it to be an updated and improved version of the Wikipedia article that is then re-integrated into Wikipedia (like [[w:Rotavirus|Rotavirus]], etc), or whether you'd prefer it to be a companion piece to the Wikipedia article that is a teaching or explanatory aid. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:48, 4 December 2017 (UTC) :I definitely prefer "a companion piece to the Wikipedia article that is a teaching or explanatory aid". Here is why. :What really is to be re-integrated? Ozob's contribution (mostly inspired by the anonymous referee) is already there. My "Spaces and structures" and "Mathematical spaces in science and engineering" (mostly inspired by Marshall Sumter)? Yes, these could be added to WP, which however would be far not a historic event, anyway. :In contrast, "a companion piece" precedent, if gets traction, has a chance to be a historic event. Here is why. :Wikipedia's goal "to inform, but not teach, wide public" is definitely unattainable in mathematics, and maybe in hard sciences. You cannot inform wide public that "a continuous function on a closed interval is bounded" without teaching the meaning of these words in this context, with informal explanations of the intuition, examples etc. :For now, mathematical articles on WP either violate the rules, or rightly revolt people; usually do both, as a compromise. :If "Spaces in Mathematics" will become a companion piece linked from "Space (mathematics)", let the latter be challenged, the "types of spaces" section removed, etc. I could be the first to attack it, though I'm afraid others would revert me. Anyway, then the tight knot could begin to unravel, globally. And the expertise of authors, referees and editors of WikiJSci could be used in full strength. Verifiability in the (very restrictive) WP sense need not hold for articles, lectures, textbooks, essays etc (since these are not something that "anyone can edit"). [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 07:17, 4 December 2017 (UTC) == An observation about mathematics and Wikipedia rules == There are very few featured articles on mathematics in Wikipedia. Taking the list from [[w:WP:WPM#Recognized content]], excluding biographies, history, and articles that are more physical than mathematical, I got about 9 articles (out of about 16,000). Now, looking at [[w:1 − 2 + 3 − 4 + ⋯|one of most interesting to me]] of these 9, I see "citation needed" 3 times, and "clarification needed" once. Well, others are "clean" (probably); but two of them are very elementary. Anyway, generally, mathematicians prefer not to pursue the almost infeasible goal of being featured. [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 21:46, 30 November 2017 (UTC) == Thank you for your work on the Wiki Journal of Science == I will delete all reference to WJS in [[How_things_work_college_course/Quantum_mechanics_timeline]], after [https://en.wikiversity.org/w/index.php?title=How_things_work_college_course%2FQuantum_mechanics_timeline&type=revision&diff=1786688&oldid=1707257 your decision] to decline it. I have had many article submissions declined in my life, but this is the first time I immediately concurred with the journal's decision (although it is not uncommon for me to agree with such decisions after pondering things a bit.) I copied the format for what is now the WJS from the WJM because I strongly believe in the importance of such journals. But I teach full time, and need to pursue a slightly different track, which is to give students graded credit for improving a course. OpenStax college has provided [[w:Open educational resources|OER]] textbooks most of my courses, but unfortunately without that labor-saving exam bank, I expect that only a limited number of instructors will be adopting these textbooks. To see an example of how we can fix this, see [[:File:Anonymous Life in the Universe.pdf|this student effort]]. When I see a student effort appropriate for WJS I will certainly recommend that they submit an article. --[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 15:30, 3 December 2017 (UTC) :{{re|Guy vandegrift}} Thank you for your message. I realise that the project has evolved significantly from its original inception. Although the journal aspect ended up matching more closely to WikiJMed, I see the value of what you're working towards. Very best of luck with your courses, and I look forward to any student works that get submitted. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:33, 3 December 2017 (UTC) == Radiocarbon dating == Have you or Brian Whalley found a second reviewer? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 19:50, 1 January 2018 (UTC) :{{re|Marshallsumter}} Sadly not. [[User:Jacknunn|Jack Nunn]] has also offered to ask a suitably qualified contact of his, but any additional referees that you're able to gather would be very helpful. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:51, 2 January 2018 (UTC) ::I've sent an email via ResearchGate to Professor A. J. Timothy Jull, Editor-in-Chief, of ''Radiocarbon'' to ask if he or one or two of his Editorial Board members would be willing to submit a review or two, or suggest possible reviewers. I'll let you know the results. I also gave him the url here for your talk page. --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 17:27, 2 January 2018 (UTC) == CSS == Just FYI. When you imported the Wikipedia versions of Template:Navbox, Template:Navbar, Module:Navbox, and Module:Navbar, it broke the local display of those items. I didn't figure out why or how until this week, and I wasn't able to fix it until this evening. Those templates depend on custom CSS styles that were in [[Wikipedia:MediaWiki:Common.css]] but were not included here. I copied the Wikipedia Common.css file in it's entirety and loaded it as the first thing in our [[MediaWiki:Common.css]] file. Any local styles that come after will override Wikipedia settings. There's obviously going to be redundancy, but unless someone is willing to go through and clean up local styles we don't need, this is the best we can do. I had never encountered this before, but it's now something to be aware of. When replacing local templates, we need to be sure to use something that transcludes the template and view before and after import to make sure it doesn't break anything or miss styling. [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 04:17, 6 January 2018 (UTC) :{{re|Dave Braunschweig}} Thank you for notifying me. So sorry that it messed up some of the existing CSS. I'll check more carefully whether imported templates and modules overwrite existing elements from now on. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 12:42, 6 January 2018 (UTC) == Editorial board tends to infinity? == "Section 3. Appointment<br> (a) The number of Editorial Board Members of Wiki.J.Sci. should be kept at a minimum of 10 and a maximum of 20."<br> (From Bylaws#ARTICLE_III). Nevertheless I see 25 members. Do I miss something? [[User:Tsirel|Boris Tsirelson]] ([[User talk:Tsirel|discuss]] • [[Special:Contributions/Tsirel|contribs]]) 09:47, 21 April 2018 (UTC) ::{{re|Tsirel}} Thank you for notifying me! It had completely escaped my mind that we'd put size limits in the bylaws. I shall absolutely bring that up for discussion. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 12:14, 21 April 2018 (UTC) ::{{re|Tsirel}} I suggest that we change the bylaws and have at least 30 people - I'm on the Editorial Board for another journal and that is a very long list - the more the merrier! (https://researchinvolvement.biomedcentral.com/about/editorial-board) [[User:Jacknunn|Jacknunn]] ([[User talk:Jacknunn|discuss]] • [[Special:Contributions/Jacknunn|contribs]]) 13:35, 30 January 2019 (UTC) == Sorry about misspelling your nickname== I called you Evo^2, when the ampersand suggests the simpler 2Evo. See https://en.wikiversity.org/w/index.php?title=Talk%3AWikiJournal_of_Science&type=revision&diff=1859146&oldid=1859076 -[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 01:18, 25 April 2018 (UTC) :{{re~Guy vandegrift}} Heh, I missed this when you first posted it - Looks like the the untaken options are rapidly running out: https://www.biosculpture.com.au/products/evo2/ https://www.evosq.co/ == I have begun to seriously edit Draft: A card game for Bell's theorem and its loopholes == I started with the comments from the third reviewer because their effort was the most meticulous. I spent a lot of time on the first paragraph and will take a 24 hour break and to other things while I ponder this. Feel free to comment if you have time. But if you are busy, do not hesitate to wait a bit. --[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 22:38, 2 May 2018 (UTC) *See [[Draft talk:A card game for Bell's theorem and its loopholes#Author's_final_(?)_response_begins_here.]] *See also [[Draft:A card game for Bell's theorem and its loopholes/Guy vandegrift]]--[[User:Guy vandegrift|Guy vandegrift]] ([[User talk:Guy vandegrift|discuss]] • [[Special:Contributions/Guy vandegrift|contribs]]) 22:44, 2 May 2018 (UTC) ::{{re|Guy vandegrift}} Thanks for the note. I'll read through the comments as they stand this evening. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:28, 6 May 2018 (UTC) == [[ShK toxin: history, structure and therapeutic applications for autoimmune diseases]] == Should we include doi links in the references? [[User:OhanaUnited|<b>{{font|color=#0000FF|OhanaUnited}}</b>]][[User talk:OhanaUnited|<b>{{font|color=green|^{Talk page}}}</b>]] 02:21, 18 May 2018 (UTC) :{{re|OhanaUnited}} Yes, when possible. I think I citoid generated a few from the PMIDs and it doesn't always find the doi. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:09, 18 May 2018 (UTC) :: I believe the author added some references[https://en.wikiversity.org/w/index.php?title=ShK_toxin%3A_history%2C_structure_and_therapeutic_applications_for_autoimmune_diseases&type=revision&diff=1867672&oldid=1867515] (including at least one that was identified as unused). And now it messes up the numbering of the reference names. [[User:OhanaUnited|<b>{{font|color=#0000FF|OhanaUnited}}</b>]][[User talk:OhanaUnited|<b>{{font|color=green|^{Talk page}}}</b>]] 21:15, 19 May 2018 (UTC) ::: Thank you for letting me know. I've sent the authors an email to explain the cite function. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:17, 20 May 2018 (UTC) == WikiJournal Main Page Representation == Any thoughts on how to add WikiJournal to [[Wikiversity:Main Page]]? -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 15:08, 10 June 2018 (UTC) :{{re|Dave Braunschweig}} So currently articles are mentioned in the [[news]] section, but I'd love a permanent presence on the main page. Do you have an idea of how much real-estate on the mainpage you'd think appropriate? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:40, 11 June 2018 (UTC) ::There are a variety of options available. WikiJournals could be added to the banner. Individual WikiJournals could be added as Featured Projects and Educational Pictures. With some type of redesign, a separate block could be added for WikiJournals, similar to either the Wikipedia or Wikibooks main pages. I don't want to limit creativity. Something should certainly be done. What may depend as much on available time to redesign or add content as anything else. I've got a lot on my plate for the summer, so if it's up to me, I would just be able to add WikiJournals to the banner. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:49, 11 June 2018 (UTC) :::{{re|Dave Braunschweig}} Thanks! I'll draft a possible template later this week. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 03:07, 12 June 2018 (UTC) ::::{{re|Dave Braunschweig}} I've been experimenting with a few possibilities at [[Main_Page/Journals]]. What to you reckon? I think it best to omit the journal logos, but perhaps include a random selection from a gallery of images? Maybe a link to random article from the back-catalogue? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 04:24, 27 June 2018 (UTC) :::::You can plug it into [[Wikiversity:Main_Page/Sandbox]] to figure out the layout. Visuals are good, something that changes every day is also good. At some point I'd like to switch the main page to a grid / flexbox design. Maybe this is a good excuse for doing that. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:33, 28 June 2018 (UTC) ::::::{{re|Dave Braunschweig}} I agree, flexbox formatting is amazing (I finally got around to using it for the menu tabs of {{tlx|article info}} so that they can be read on mobiles). There have also been some developments over at Wikipedia in [[wikipedia:Wikipedia:WikiProject_Portals|automated templates for portals]]. I've done some experiments in [[Wikiversity:Main_Page/Sandbox]]. Still not certain over the best layout. probably 33% width or 50% width will be best. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:08, 28 June 2018 (UTC) {{re|Dave Braunschweig}} I've had a go at a flex box based implementation in the [[Wikiversity:Main_Page/Sandbox]] now that I've sort of got the hang of it from working on [[Template:WikiJMed formats]]. Have a look and see what you think. It's not perfect, but shouldn't need too much further tweaking! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 09:11, 6 July 2018 (UTC) :I wonder if a two-column layout, similar to [[Wikipedia:Main Page]] would be better. There's something about the current flex design that isn't working correctly with image overlap. On my screen today, News is covering 15% of The Last Supper. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:51, 7 July 2018 (UTC) :Two-column seems better from a mobile perspective. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 01:44, 8 July 2018 (UTC) == Wikipedia links == I've created [[WikiJournal_Preprints/Ice_drilling|a preprint for ice drilling]], just by pasting in the Wikipedia wikitext, but I can see a lot of tweaking is needed. For example, the links need to change from e.g. <nowiki>[[glacier]] to [[wikipedia:glacier|glacier]]</nowiki>. Is there a script for this, or does one have to tweak each by hand? And is there a checklist of other changes that need to be made? [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 12:54, 23 June 2018 (UTC) :{{re|Mike Christie}} One of our next projects is sorting out an automated way to convert wikilinks to and files into the {{tlx|fig}} format. Currently the figures have to be done manually, but the wikilinks are switched by find-replace with regular expressions: :#<code><nowiki>\[\[([^\|]*?)\]\]</nowiki></code> replace with <code><nowiki>[[w:\1|\1]]</nowiki></code> :#<code><nowiki>\[\[([^\:]*?)\]\]</nowiki></code> replace with <code><nowiki>[[w:\1]]</nowiki></code> :Would you be able to update the information in the article info template at the top and update the fig formatting (most important is the attribution paramter). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:59, 23 June 2018 (UTC) ::Will do; have had to work this weekend and am away next weekend so I will try to get it done one night this week. Thanks for the wikilink fix. [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 20:42, 24 June 2018 (UTC) :::Done. I've submitted the authorship declaration; let me know anything else I need to do. Thanks. [[User:Mike Christie|Mike Christie]] ([[User talk:Mike Christie|discuss]] • [[Special:Contributions/Mike Christie|contribs]]) 10:20, 28 June 2018 (UTC) == Custodianship == Congratulations! You are now a custodian! You should see more tools in [[Special:SpecialPages]]. See [[Wikiversity:Custodian Mentorship]] for a list of custodian skills you should become comfortable with. First up are the following: # Edit [[MediaWiki:Sitenotice]] and clear the current site notice. # Edit [[Wikiversity:Support staff]] and update your role. Let me know whenever you have any questions. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 13:22, 24 June 2018 (UTC) :{{re|Dave Braunschweig}} The documentation is clear so far, but I'll message you if I've any questions. Thank you for your help so far, and as I said in the application, I aim to start out particularly cautious so as not to break anything. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:44, 24 June 2018 (UTC) == Image scaling == Hello. Trouble with display of image at main WikiJournal of Medicine (COPE logo for WikiJMed) - it is displaying in too large a way despite specifying 80px in template. [[User:RubberBandHoot|RubberBandHoot]] ([[User talk:RubberBandHoot|discuss]] • [[Special:Contributions/RubberBandHoot|contribs]]) 02:09, 18 November 2018 (UTC) :{{re|RubberBandHoot}} Thanks for letting me know! The issue seems to be because the {{tlx|WikiJMed_right_menu}} is still built as a table, rather than using the more robust css div formatting. I've used a simpler type of image formatting, which seems to work better. Eventually, I'll update the template's formatting which should make it more future-proof. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:23, 18 November 2018 (UTC) ::{{re|Evolution and evolvability|T.Shafee(Evo&#65120;Evo)}}. Thank you. [[User:RubberBandHoot|RubberBandHoot]] ([[User talk:RubberBandHoot|discuss]] • [[Special:Contributions/RubberBandHoot|contribs]]) 12:53, 18 November 2018 (UTC) == second peer review == Hello Dr. Shafee, just wanted to let you know Ive done the second peer review[https://en.wikiversity.org/wiki/Talk:WikiJournal_Preprints/West_African_Ebola_virus_epidemic] however [[WikiJournal_of_Medicine/Potential_upcoming_articles]] the 'stage' number doesn't reflect that yet, thanks--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:50, 15 December 2018 (UTC) ::{{re|Ozzie10aaaa}} - updated! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:09, 15 December 2018 (UTC) :::thanks--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 23:17, 15 December 2018 (UTC) ===further reviews=== Hi Dr. Shafee, just wanted to let you know Ive done both reviews for [[Talk:WikiJournal_Preprints/Hepatitis_E]] and [[Talk:WikiJournal_Preprints/Dyslexia]] however [[WikiJournal_of_Medicine/Potential_upcoming_articles]] the 'stage' number doesn't reflect that yet, thanks (and Merry Xmas!)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 21:00, 23 December 2018 (UTC) :{{re|Ozzie10aaaa}} Thanks for letting me know! I've updated the tracking table. We are expecting 1-2 more reviews for each of the articles in January. Happy New Year! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:38, 31 December 2018 (UTC) ::thank you(Happy New Year to you!)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 11:36, 31 December 2018 (UTC) :::Thank you Thomas and [[User:Ozzie10aaaa|Ozzie10aaaa]], and Happy New Year! [[User:Mikael Häggström|Mikael Häggström]] ([[User talk:Mikael Häggström|discuss]] • [[Special:Contributions/Mikael Häggström|contribs]]) 15:32, 31 December 2018 (UTC) ===final review=== Hi Dr. Shafee ,[[WikiJournal Preprints/Western African Ebola virus epidemic]]..done, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 03:08, 14 January 2019 (UTC) :[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Potential_upcoming_articles&diff=1965407&oldid=1964778]thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:26, 14 January 2019 (UTC) ===Hep E, final review=== Dr. Shafee, sorry to bother you however I was going over [https://upload.wikimedia.org/wikiversity/en/b/b2/WikiJournal_Preprints_Hepatitis_E_corr._pischke.pdf]and aside from a modest(13) amount of circles(red), it gives little in the way of what the reviewer wants,I suppose I could assume to check references to the statements but upon looking at the section on ''classification'' there are 'two circles' in no particular area that don't seem to indicate anything at all?...please advise, thank you (I have 'clicked' each circle with my mouse, not certain how this works)--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 14:50, 15 January 2019 (UTC) *<u>have figured out, downloaded on PDF and then comments appear</u>, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 18:01, 15 January 2019 (UTC) :*{{re|Ozzie10aaaa}} Good point - it's not immediately obvious to look for the annotations in a PDF. I've been trying to find a way to export them so that they can be pasted in the Wikimarkup as well, but I've not yet found a way. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:30, 15 January 2019 (UTC) ::*[[WikiJournal Preprints/Hepatitis E]]...done, thank you Dr.Shafee--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 02:06, 16 January 2019 (UTC) :::*Thanks. I'll let you know when the next steps are done on our end. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:29, 16 January 2019 (UTC) ::::Dr. Shafee, done (again)[https://en.wikiversity.org/w/index.php?title=Talk:WikiJournal_Preprints/Hepatitis_E&diff=1966248&oldid=1965957] thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 02:06, 17 January 2019 (UTC) :::::[[Talk:WikiJournal_Preprints/Hepatitis_E#Editorial_comments]] done--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:18, 30 January 2019 (UTC) ===Ebola=== Dr.Shafee, done [[Talk:WikiJournal Preprints/Western African Ebola virus epidemic]], thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 05:19, 23 January 2019 (UTC) :Done [https://en.wikiversity.org/w/index.php?title=Talk:WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1969876&oldid=1969748], thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 07:39, 27 January 2019 (UTC) ::{{re|Ozzie10aaaa}} Thanks. One final minor thing: There are a mix of {{tlx|Cite_web}} and {{tlx|Cite_neews}} templates used used for WHO, BBC etc. Would it be sensible to distinguish different types of source with {{tlx|Cite_web}}/{{tlx|Cite_report}}/{{tlx|Cite_news}}? Not vital, but could be useful for distinguishing in the metadata. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:13, 31 January 2019 (UTC) :::The logical answer is yes, it would because they are different {{tlx|Cite_web}}/{{tlx|Cite_report}}/{{tlx|Cite_news}}, how should we proceed?--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 05:28, 31 January 2019 (UTC) ====per suggestion==== Dr Shafee per your email, Ive done the following: 1. have added the reference {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983339&oldid=1970572 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} 2. have gone thru the indicated 'media' references- :*'''26,28,29''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983345&oldid=1983342 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} :*'''36''', reference was simply redone to <u>the direct link</u> {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983353&oldid=1983345 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}}...''Doctors Without Borders'' which is a NGO. :*'''42''',{{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983361&oldid=1983353 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} :*'''47''' replaced with [https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00259-5/fulltext The Lancet Post Ebola syndrome] :*'''54''', '''55''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983557&oldid=1983556 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''56''' reference/text <u>deleted</u> [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983556&oldid=1983490 did not add significantly to paragraph] :*'''61''', '''62''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983559&oldid=1983557 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''69''' replaced <u>with United nations</u> {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983581&oldid=1983559 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''74-79''' - have slightly altered as follows (''Resistance to interventions by health officials among the Guinean population remained greater than in Sierra Leone and Liberia, per media reports, raising concerns over its impact on ongoing efforts to halt the epidemic; in mid-March, there were 95 new cases and on 28 March, and a 45-day "health emergency" was declared in 5 regions of the country.[71][72] On 22 May, the WHO reported another rise in cases, per media reports,[73] which was believed to have been due to funeral transmissions;[74] on 25 May, six persons were placed in prison isolation after they were found travelling with the corpse of an individual who had died of the disease,[75] on 1 June, it was reported that violent protests in a north Guinean town at the border with Guinea-Bissau had caused the Red Cross to withdraw its workers.[76] '') diffs are available at history[https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&action=history] :*'''81''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983594&oldid=1983591 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''84''' ? :*'''85''' was replaced with {{cite web |title=Ebola Situation Report - 11 November 2015 {{!}} Ebola |url=http://apps.who.int/ebola/current-situation/ebola-situation-report-11-november-2015 |website=apps.who.int |accessdate=6 March 2019}} :*'''86''', '''87''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983606&oldid=1983605 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} :*'''90''', '''92''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983611&oldid=1983606 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}}...deleted reference 92/minor text :*'''93'''? :*'''94'''? (same sentence) :*'''95, 96, 98, 99''' {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983639&oldid=1983635 |website=en.wikiversity.org |accessdate=6 March 2019 |language=en}} 3. have trimmed '''50''' and '''58''' press release {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=1983341&oldid=1983339 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} and {{cite web |title=Difference between revisions of "WikiJournal Preprints/Western African Ebola virus epidemic" - Wikiversity |url=https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Western_African_Ebola_virus_epidemic&diff=next&oldid=1983341 |website=en.wikiversity.org |accessdate=5 March 2019 |language=en}} I want to thank you for your kind suggestions--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 17:26, 6 March 2019 (UTC) == Lint Errors == See [[Special:LintErrors/misc-tidy-replacement-issues]]. There are issues in several of the WikiJournal templates. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 03:10, 28 December 2018 (UTC) :{{re|Dave Braunschweig}} Thanks. I've tracked the div-span-flip error to the {{tlx|WikiJournal_top_menu}} template. Should be easy to fix once I root it out within that template. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:26, 28 December 2018 (UTC) ::{{re|Dave Braunschweig}} Fixed. It was a set of spans in the {{tlx|WikiJournal_top_menu_bar}} and {{tlx|Annotated_image_4}} templates. I've manually purged a few pages to check that it also fixes the downstream templates and pages. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:58, 29 December 2018 (UTC) See [[Special:LintErrors/html5-misnesting]]. There is an issue in [[Template:Editor's comments]]. Thanks! -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 03:12, 2 April 2019 (UTC) ==[[Lysenin]] article== Thomas, the article needs thorough copy-editing. Someone tagged it for citation style but it's not unclear, just not in any template. The article is written assuming considerable knowledge of cell biology and might need quite substantial glossing to make it easier to read. I've added numerous wikilinks and fixed a few bits of English that urgently needed attention, but much more is needed. Cheers, Ian [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 09:14, 6 February 2019 (UTC) :{{re|Chiswick Chap}} Good point. Upon re-reading I see what you mean about the over-technicality - that is definitely something the author can address. Would you be happy to add a comment to the submission's talkpage? The language aspects often need assistance from others, since the author is probably working at the limit of their English skills. It would good to do at least a quick copyedit run before contacting peer reviewers. Otherwise I'll summarise and add to mine. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:26, 6 February 2019 (UTC) :: OK, I've added a comment and made a (very) preliminary copy-edit of the article. --[[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 01:56, 7 February 2019 (UTC) == Final review == Dr, Shafee I noticed that the Dyslexia peer-review has been indicated for sometime in February [[WikiJournal_of_Medicine/Potential_upcoming_articles]], was wondering if there might be a difficulty with it since its almost the end of the month, thank you--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:32, 21 February 2019 (UTC) :{{re|Ozzie10aaaa}} Thanks for the note. I'll check with its [[WikiJournal of Medicine/Potential upcoming articles|review coordinators]] (Eric Youngstrom, Jitendra Kumar Sinha). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:04, 8 March 2019 (UTC) ::thank you, Dr Shafee, I am watching the article in question for any updates that need to be addressed... thank you again--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 13:46, 21 March 2019 (UTC) == tl:Cite book lua error == I noticed that you imported newer revisions of {{tl|Cite book}}. There is a "lua error" which is triggered by "coauthors=last, first" and the error goes away if the name is removed. I'm not sure what is causing the or how to fix it. The error is visible in Example 1 at the template page. --[[User:Mu301|mikeu]] ^{[[User talk:Mu301|talk]]} 18:10, 10 March 2019 (UTC) :{{re|Mu301}} I've had a look at the relevant line of [[Module:Citation/CS1]] and can't find what's causing the error, so I've asked for assistance over at the MediaWiki support desk ([https://www.mediawiki.org/wiki/Topic:Uwduy1hmnz6taq9d Topic:Uwduy1hmnz6taq9d]). Will aim to get fixed ASAP. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:22, 21 March 2019 (UTC) I noticed a similar error in {{tl|coord}} which I have [https://en.wikiversity.org/w/index.php?title=Template:Coord&diff=1992448&oldid=1951967 temporarily downrev'd to an earlier version]]. I've brought up the topic of template imports at [[Wikiversity:Colloquium#template_import]]. I'll follow up there. I'm a little concerned about the long term maintainability of these imported templates. --[[User:Mu301|mikeu]] ^{[[User talk:Mu301|talk]]} 11:51, 30 March 2019 (UTC) == WikiJournal preprints/Ice drilling technology == Hi Evolution and evolvability! Professor Taylor is mentioning in his follow up that the original title "Ice drilling" or another alternative suggested by the authors "Ice drilling methods" is okay. Should we give the authors time to reconsider? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:25, 9 April 2019 (UTC) == Widgiemoolthalite et al. == Hey Evolution and evolvability, Thanks for all your work on the WikiJournal projects! I had a question about [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Widgiemoolthalite&oldid=2003670 your edit] to the [[WikiJournal Preprints/Widgiemoolthalite|Widgiemoolthalite preprint]] at ''WJS''. I checked through the article's history and while it was imported from Wikipedia, I don't believe the [[WikiJournal_User_Group/Publishing#Acknowledgement_of_sources|>10% or 1 paragraph]] threshold for work contributed by other editors was met, which is why I left the link to the article's contributors in the Acknowledgements rather than as an ''et al.'' link. Was I correct in doing this? Thank you kindly! Best, [[User:Bobamnertiopsis|Bobamnertiopsis]] ([[User talk:Bobamnertiopsis|discuss]] • [[Special:Contributions/Bobamnertiopsis|contribs]]) 03:33, 7 May 2019 (UTC) :{{re|Bobamnertiopsis}} Aha, thank you. You are correct, I had not noticed the attribution section. Thank you for checking. Please feel to remove the {{para|et al}} parameter. You already correctly added the <code><nowiki>|license={{CC-BY-SA work}}</nowiki></code>, so that should all be fine! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:48, 7 May 2019 (UTC) ::Fabulous, thank you! [[User:Bobamnertiopsis|Bobamnertiopsis]] ([[User talk:Bobamnertiopsis|discuss]] • [[Special:Contributions/Bobamnertiopsis|contribs]]) 16:11, 7 May 2019 (UTC) Hi Evolution and evolvability, Is this review date "2015-12-31" correct for Robert Hazen's review? It appears to predate the article's existence on Wikipedia? --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 14:44, 14 May 2019 (UTC) :{{re|Marshallsumter}} Thank you for notifying me. For some reason the date parameter was omitted so the template put in a default. I've updated the date, and edited the template so that it doesn't do something so misleading! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 23:29, 14 May 2019 (UTC) == Reviewer credentials == Hey Thomas, I got a question for you. While [https://en.wikiversity.org/w/index.php?title=Talk%3AWikiJournal_of_Science%2FA_card_game_for_Bell%27s_theorem_and_its_loopholes&type=revision&diff=2030070&oldid=2008763 entering the credentials] of the reviewer's institution, should we use the institution's native name or translated English name? That example is perfect as one is French and the other is German, yet both are easy to understand even if you don't know a single word in French or German. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 00:00, 9 July 2019 (UTC) ::{{re|OhanaUnited}} I'd go for the original language when in doubt to avoid any possibly ambiguity from alternative possible translations (unless it is more well known my its translation e.g. "Max Planck Institute of Biochemistry"). The priority is for it to be unambiguously identifiable, so even putting the translation with the original in brackets could work when it seems useful. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:22, 9 July 2019 (UTC) ==Paper== Thomas, I tried replying by email but it bounced saying unusual spamming from my IP! I copyedited the paper as requested; I hope not to have changed any meanings, so perhaps your expert eye would be beneficial for a final check. [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 12:45, 8 August 2019 (UTC) :{{re|Chiswick Chap}} Fantastic, thank you! I've had look through the new version and the diffs and it's a great improvement.I'll do an additional sweep through before confirming with the author that they're ok wth the edits. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 16:58, 8 August 2019 (UTC) == [[WikiJournal of Medicine/Medical gallery of Mikael Häggström 2014]] == I'm not quite sure how to troubleshoot the category error in question on this page. And I have not seen this kind of error before. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 15:12, 22 August 2019 (UTC) :{{re|OhanaUnited}} Very odd. I'll get on that - thanks for the note. It should just be placing it in [[:Category:Articles_submitted_for_peer_review_in_2014]] based on the {{para|submitted}} year. I'll dig into the {{tlx|Article info main}} code to find the error. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:23, 24 August 2019 (UTC) ::Super weird. there's some secret difference between the characters "2014‎" and "2014". I think some hidden zero-width space character? Should be fixed now anyway. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 14:11, 24 August 2019 (UTC) ::: It seems more common than I thought. Here's [[Talk:WikiJournal of Science/Baryonyx#Additional peer review on Wikipedia|another page]] with similar error. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 02:18, 26 August 2019 (UTC) ::::{{re|OhanaUnited}} Rats. The fix is to check if there's a zero-width space before or after the date and remove it. I'll go through to check some others. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:20, 26 August 2019 (UTC) ::::{{re|OhanaUnited}} I think I've found them all, so that should be fixed now. Thanks again for spotting the initial problems! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 05:28, 27 August 2019 (UTC) ::::: There's one more: [[Talk:WikiJournal of Medicine/Medical gallery of Blausen Medical 2014#Second peer review - intracranial electrodes]] [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 04:01, 1 September 2019 (UTC) == Community Insights Survey == <div class="plainlinks mw-content-ltr" lang="en" dir="ltr"> '''Share your experience in this survey''' Hi {{PAGENAME}}, The Wikimedia Foundation is asking for your feedback in a survey about your experience with {{SITENAME}} and Wikimedia. The purpose of this survey is to learn how well the Foundation is supporting your work on wiki and how we can change or improve things in the future. The opinions you share will directly affect the current and future work of the Wikimedia Foundation. 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This survey is hosted by a third-party and [https://foundation.wikimedia.org/wiki/Community_Insights_2019_Survey_Privacy_Statement governed by this privacy statement] (in English). Find [[m:Community Insights/Frequent questions|more information about this project]]. [mailto:surveys@wikimedia.org Email us] if you have any questions, or if you don't want to receive future messages about taking this survey. Sincerely, </div> [[User:RMaung (WMF)|RMaung (WMF)]] 19:13, 20 September 2019 (UTC) <!-- Message sent by User:RMaung (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=CI2019List(other,act5)&oldid=19395141 --> == Reminder: Community Insights Survey == <div class="plainlinks mw-content-ltr" lang="en" dir="ltr"> '''Share your experience in this survey''' Hi {{PAGENAME}}, There are only a few weeks left to take the Community Insights Survey! We are 30% towards our goal for participation. If you have not already taken the survey, you can help us reach our goal! 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Sincerely, </div> [[User:RMaung (WMF)|RMaung (WMF)]] 17:04, 4 October 2019 (UTC) <!-- Message sent by User:RMaung (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=CI2019List(other,act5)&oldid=19435548 --> == Radiocarbon dating == Hi Thomas. ''British Archaeology'', the journal of the [https://en.wikipedia.org/wiki/Council_for_British_Archaeology Council for British Archaeology], has a box in each issue recommending the Wikipedia article on radiocarbon dating for information on the subject. Last month, I wrote to the journal informing them of the WJS article and they have published my letter in the November/December 2019 issue and changed to recommending the WJS version. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|talk]]) 14:34, 10 October 2019 (UTC) :{{re|Dudley Miles}} Very interesting! Thank you for both contacting them and for your post here and on the wikipedia article's talkpage. It's an idea that might be cross-applicable to other journals and magazines on different topics. Would you be willing to send me the email text that you sent? [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:29, 11 October 2019 (UTC) ::I have forwarded the email to you. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 08:25, 11 October 2019 (UTC) == started an article == heya I have started putting an article together [[user:Faendalimas/What_is_in_a_Name]], it is based on a plenary speech I gave at an international conference in 2018, many people have been asking me to publish it. So I am writing it out, would appreciate your thoughts. Cheers [[User:Faendalimas|<span style="color: #004730">Scott Thomson</span>]] (<small class="nickname">Faendalimas</small>) ^{[[User talk:Faendalimas|<span style="color: maroon">talk</span>]]} 00:50, 3 November 2019 (UTC) :{{re|Faendalimas}} In general, we've avoided opinion articles to prevent the risk of either a) the article can't really be peer reviewed or b) the journals look like just a blogging site which could undermine the other articles. However ''really'' the distinction is whether an article could be reasonably peer reviewed. I think if the article can be written as a case study and proposal then that probably can be put to reviewers as to whether e.g. the relevant background and related work is clearly described, the current issues are accurately put forward, the proposal addresses the issues raised and the case is convincingly made. It'd have to be put to the other board members since it is still different from anything previously published in the journals. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:19, 3 November 2019 (UTC) == Re: Maps via Wikidata == Very nice. I was wondering if it can be loaded directly when user visits a page (kind of like my current [[User:OhanaUnited/sandbox|sandbox]]). Another thing is if there's a way to manually specify the location. For instance, the map directly loads my employer's headquarter location (Ottawa) even though I'm in Toronto. And do you know why the map shows my profile twice in Ottawa? I couldn't quite figure it out. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 22:35, 23 November 2019 (UTC) :So I've asked over at [[Wikidata:Wikidata:Project_chat#Embedding_query_result_in_wikimedia_page]], but there was no obvious answer. Maybe there's some location to ask over at wikivoyage, where they probably have more experience with such things? Otherwise, on other pages I've just included a screenshot that links to the live query ([[metawiki:Wikimedian_in_residence|example]]). The way I'm c alculating location is to just use the listed location of the employer (easiest to see in the [https://w.wiki/Ccf table output of the same query]), but there might be a way to check whether a location is listed for the person themself. Your double listing on {{q|Q22674854}} was an error that I've now fixed. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:49, 24 November 2019 (UTC) == wikipediajournal.com == Hi. Would you be willing to make me an account on wikipediajournal.com? I'd like to try some of the extensions there, and see if I have any ideas for user scripts that'll help the project. Thanks, --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 09:36, 2 December 2019 (UTC) :{{re|DannyS712}} Thanks! I think that should be fine What sorts of extensions are you thinking? Pinging {{u|Bryandamon}} who set the test wiki up. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 10:27, 2 December 2019 (UTC) ::I was just going to test what is installed already --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 11:10, 2 December 2019 (UTC) :::{{Re|DannyS712}} Sounds excellent. I've asked bryan to add you (currently beyond my knowledge). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 11:35, 2 December 2019 (UTC) :::{{Re|DannyS712}} Should be done now. Let me know if it's not working and I'll follow-up. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:39, 2 December 2019 (UTC) ::::It worked, thanks --[[User:DannyS712|DannyS712]] ([[User talk:DannyS712|discuss]] • [[Special:Contributions/DannyS712|contribs]]) 00:27, 3 December 2019 (UTC) == [https://en.wikiversity.org/w/index.php?title=WikiJournal_Preprints/Abū_al-Faraj_al-Iṣfahānī&diff=next&oldid=2107575 This edit] == Hi. Please look at the above linked edit. I think you may have accidentally changed the words to be incorrect. [[User:Vermont|Vermont]] ([[User talk:Vermont|discuss]] • [[Special:Contributions/Vermont|contribs]]) 12:02, 17 December 2019 (UTC) == Italicizing title == I understand that [https://en.wikiversity.org/w/index.php?title=Template:Article_volume_summary&diff=2014069&oldid=2013542 you added italics parameter] to {{tl|Article volume summary}}. I think we need a different approach. If we set italics=yes in the template, the entire title is italicized, including parts that should not be italicized.[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Volume_4_Issue_1&diff=prev&oldid=2124525] If I use wiki markup directly in the title,[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Volume_2_Issue_1&diff=2124526&oldid=1716339] it breaks the link in the title and the full-text link. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 07:05, 22 February 2020 (UTC) :Have a look at [[WikiJournal Preprints/Abū al-Faraj ʿAlī b. al-Ḥusayn al-Iṣfahānī, the Author of the Kitāb al-Aghānī|this page]] which might have a solution. The code below should work on the page. I'll add a {{para|display_title}} parameter to the [[template:Article volume summary|relevant template]] that's used on the volume/issue page. <pre> {{DISPLAYTITLE:<span style="font-family:Century Gothic, Helvetica, sans serif; font-size: 10pt">{{BASEPAGENAME}}</span><span style="color:#DDD">/</span><span style="font-family:Century Gothic, Helvetica, sans serif;">Images of </span><span style="font-family:Century Gothic, Helvetica, sans serif;font-style:italic;">Aerococcus urinae</span>}} </pre> :[[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:35, 22 February 2020 (UTC) == Template:Information and Wikidata == Something about the changes to [[Template:Information]] is incomplete. The three files you added are showing up in [[:Category:Files with no machine-readable author]], [[:Category:Files with no machine-readable description]], and [[:Category:Files with no machine-readable source]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 19:54, 23 May 2020 (UTC) :{{re|Dave Braunschweig}} Thanks! I've created a substitutable wrapper template {{tlx|InformationQ}} that seems to solve it! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:36, 24 May 2020 (UTC) == Adding a file in response to reviewer == Hi Thomas, could I ask you to have a quick check at [[Talk:WikiJournal Preprints/Beak and feather disease virus]]? The authors have made updates to the article based on the reviewer comments, and also provided a change-tracked document of these. I couldn't figure out an elegant method to attach that - the {{tl|response}} template does not take a file argument. So I stuck it in as an image thumbnail, which is probably less than ideal. I suspect there's a better method? Cheers --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 16:00, 13 June 2020 (UTC) :{{re|Elmidae}} No problem - I've added a {{para|pdf}} parameter to the {{tl|response}} template, so that it can be added. Good point that it was a missing capability. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:51, 14 June 2020 (UTC) ::Ah, most well crafted :) Thanks. --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 20:20, 14 June 2020 (UTC) ==Congrats!== *[https://en.wikiversity.org/w/index.php?title=WikiJournal_of_Medicine/Applications/SCOPUS&diff=2171184&oldid=2125794 very well done]--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 22:43, 19 June 2020 (UTC) == Æthelfæd == Hi Thomas. An editor has deleted an edit at [https://en.wikipedia.org/w/index.php?title=%C3%86thelfl%C3%A6d&diff=next&oldid=971886775] which I assume you made. I will leave you to deal with it if you wish as I do not know the rules on this. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 16:04, 12 August 2020 (UTC) :{{re|Dudley Miles}} Aha, rats. Thank you for letting me know. I've also just been alerted to a related conversation all about it [[wikipedia:Wikipedia_talk:WikiProject_Medicine#Improper_use_of_template%2C_diverting_en.Wikipedia_readership|here]], so will have a read through that now and respond. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:03, 13 August 2020 (UTC) == [[:WikiJournal_of_Medicine/Alternative_layout2]] == As you seem to be responsible for a number of templates on which this depends , perhaps you can determine why this misrenders? Also why {{tl|Article info}} misrenders, generating unclosed DIV sequences... Thanks.. [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 18:20, 18 August 2020 (UTC) : There seem to be a lot of LintErrors generated despite attempts by me to fix the problem (as yet unsuccessfully). : https://en.wikiversity.org/w/index.php?title=Special:LintErrors/missing-end-tag&dir=prev&offset=482875 [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 18:22, 18 August 2020 (UTC) == You've got mail == {{You've got mail}}'''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 19:32, 22 September 2020 (UTC) == ... == Well, that wasn't all that helpful, was it :/ Sorry, wasn't aware that there was an actual "response" template. Will keep it in mind for next time! Cheers --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 14:42, 10 October 2020 (UTC) :And now I realize that we talked about that very template before, on this very page, and I still didn't remember! I need a holiday... --[[User:Elmidae|Florian <small>(Elmidae)</small>]] ([[User talk:Elmidae|talk]] · [[Special:contributions/Elmidae|contribs]]) 18:32, 11 October 2020 (UTC) == Testing out new reply to tool on my talkpage == Comment *list *list *list Comment [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:58, 15 October 2020 (UTC) :test reply [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:59, 15 October 2020 (UTC) ::Hi Thomas, it works ... PS it's under "Beta features" on people's Preferences page. Ian [[User:Chiswick Chap|Chiswick Chap]] ([[User talk:Chiswick Chap|discuss]] • [[Special:Contributions/Chiswick Chap|contribs]]) 08:42, 15 October 2020 (UTC) :::Works in Firefox on windows. [[User:J S Lundeen|J S Lundeen]] ([[User talk:J S Lundeen|discuss]] • [[Special:Contributions/J S Lundeen|contribs]]) 13:44, 15 October 2020 (UTC) == Update submitted article == We would like to rework the submitted article https://en.wikiversity.org/wiki/WikiJournal_Preprints/Androgen_backdoor_pathway Can you please point to correct path to sandbox and then resubmit? Or we may edit it now until (before) we get peer reviewers assigned? We would like to make substantial edits. ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 18:48, 26 October 2020 (UTC) :{{re|Maxim Masiutin}} Since we have not yet contacted the peer reviewers, you have two options: :#ask us to wat before contacting reviewers and update the article directly :#create a copy at https://en.wikiversity.org/wiki/WikiJournal_Preprints/Androgen_backdoor_pathway/sandbox that you can continue editing whilst reviewers comment :let me know what you prefer [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:18, 26 October 2020 (UTC) ::{{re|Evolution and evolvability}} Thank you, I have created the sandbox page at the URL that you have provided, so we can continue editing whilst reviewers comment ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 09:47, 27 October 2020 (UTC) :::{{re|Maxim Masiutin}} Ok, and thanks for adding the link to the tracking table. To confirm, the peer reviewers will be asked to review the main article page and not the /sandbox. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:44, 28 October 2020 (UTC) ::::{{re|Evolution and evolvability}} Thank you, I understand that the peer reviewers will be asked to review the main article page and not the /sandbox. ---[[User:Maxim Masiutin|Maxim Masiutin]] ([[User talk:Maxim Masiutin|discuss]] • [[Special:Contributions/Maxim Masiutin|contribs]]) 16:25, 28 October 2020 (UTC) == Self-closed tags == There's a recent error in one or more WikiJournal templates that is generating 350+ lint errors. See [[Special:LintErrors/self-closed-tag]]. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 01:55, 7 November 2020 (UTC) :@[[User:Dave Braunschweig|Dave Braunschweig]]: Aha, sorry about that. I've tracked the bug and fixed it! Was using a bit of html that I don't really understand to auto-number figures using [[template:WikiJournal/figure/styles.css]]. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 08:14, 7 November 2020 (UTC) ==COVID-19== Dr Shafee, may submit by April (depending on vaccine[https://xtools.wmflabs.org/authorship/en.wikipedia.org/COVID-19%20pandemic/])--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 14:30, 15 November 2020 (UTC) == Suggested citation format == Hello, hope you are doing well. There's a problem on all "Suggested citation format", for example see [[WikiJournal of Medicine/Viewer interaction with YouTube videos about hysterectomy recovery]]. Best '''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 00:34, 29 November 2020 (UTC) :{{re|علاء }} Thanks for spotting that! Now fixed. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 01:51, 29 November 2020 (UTC) ::Thanks! '''--'''[[User:علاء |<span style="color:black;font-family:Script MT Bold;font-size:16px;">Alaa</span> ]] [[User_talk:علاء |:)..!]] 12:18, 29 November 2020 (UTC) == Steps in [[WikiJournal of Science/Potential upcoming articles]] == Are the steps/legends still applicable now that the table is auto-populated based on Wikidata and no longer shows which stage an article is at? [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 16:26, 30 November 2020 (UTC) :{{re|OhanaUnited}} Good point. We probably still need to indicate the the general order of events, but that might be better as a schematic picture? Something like a process diagram, or a more focused, horizontal version of [[:File:WikiJournal of Science publishing pipeline (wiki first).svg|this]]. The one thing I've not worked out how to usefully automate via wikidata is when each review has been responded to, which would be needed to differentiate what was called '4,5,6'. [[metawiki:WikiJournal_User_Group/Meetings/2019-12-18|Integration with OJS]] could solve that, so it's back up the priority list for next year! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:40, 1 December 2020 (UTC) :: I think, in the interest of openness, we can mention which stage it is on under the "Notes" section. Or maybe add one column to the table to describe which it is at (without the Wikidata linkage). [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 06:27, 4 December 2020 (UTC) == et al. == According to [[Wikipedia:Category:CS1 errors: explicit use of et al.]], "et al." is no longer a valid author name. Instead, we are supposed to use <code>|display-authors=etal</code>. I'm not sure how this can be resolved using Wikidata entries, but it does need to be addressed at some point. See our own [[:Category:CS1 errors: explicit use of et al.]] for affected resources. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:32, 1 December 2020 (UTC) :{{re|Dave Braunschweig}} Yes, there was also some conversation about it over at [[wikipedia:Template_talk:Citation#Et_al|this page]]. Currently I've made a workaround in {{tlx|Cite Q EtAl}} by including a hyperlinked 'et al.' which the software doesn't recognise (a temporary cheat), but ove the cite_Q template has stabilised (still lots of changes occurring) It should be possible to implement a <code>|display-authors=etal</code>-based solution. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:47, 1 December 2020 (UTC) == License == [[:File:What are Systematic Reviews.pdf]] has copyright information but is missing a license. See [[:Category:Files with no machine-readable license]]. Perhaps you can add a License or Permission value that would include the license. -- [[User:Dave Braunschweig|Dave Braunschweig]] ([[User talk:Dave Braunschweig|discuss]] • [[Special:Contributions/Dave Braunschweig|contribs]]) 02:43, 1 December 2020 (UTC) :{{re|Dave Braunschweig}} Thanks for catching that. Fixed (both via updating wikidata, and by adding the relevant template below)! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 06:30, 1 December 2020 (UTC) == Paper status == Hi T.Shafee, My [[WikiJournal_Preprints/Affine_symmetric_group|submission]] to WJS has been sitting around for more than six months with no visible progress on refereeing. I e-mailed the assigned editor a week ago to inquire about the status of the refereeing process, but I have not received a response. I was hoping you could look into the matter. Thanks, [[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 21:34, 30 January 2021 (UTC) :{{re|JayBeeEll}} Thanks for letting me know. I'll look into it and organise a change in editor if the current editor isn't available any more. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 05:58, 31 January 2021 (UTC) :: Thank you, I appreciate it. --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 13:01, 31 January 2021 (UTC) :::{{re|JayBeeEll}} The final review is now in for the article ([[Talk:WikiJournal_Preprints/Affine_symmetric_group#Peer_review_3|link]]). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:06, 26 February 2021 (UTC) :::: Thanks! --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 00:31, 26 February 2021 (UTC) :::: I did not find a button to push to indicate that I have completed my response to the referees (and accompanying article edits); I hope that leaving this comment here is an accepted method! --[[User:JayBeeEll|JayBeeEll]] ([[User talk:JayBeeEll|discuss]] • [[Special:Contributions/JayBeeEll|contribs]]) 20:17, 18 March 2021 (UTC) :::::{{re|JayBeeEll}} Excellent, thank you. I'll notify any reviewers that asked to see the article again, and if they have no additional items, the board will vote in the coming weeks! We're hoping to make an easier to use back-end for making sure that authors, reviewers and editors can easily update an article's stage and be notified when they have the ball back in their court, but in the meantime, you're right that this not is as good a place as any! [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:35, 19 March 2021 (UTC) == [[:Template:Fig]] == Please check your logic, It's leaking a DIV in certain instances. such as in [[WikiJournal_of_Science/About]] [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 13:43, 7 February 2021 (UTC) : {{ping|Evolution and evolvability}} Did you actually want something more like the code in [[User:ShakespeareFan00/sandbox|my sandbox]] where the possibility of a 'nil' or absent 1st paramater is considered? [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 16:06, 10 February 2021 (UTC) ::{{re|ShakespeareFan00}} Thank you so much for your testing on this. I appreciate that the complexity of the structure makes it frustrating! I've been using [[Template:Fig/sandbox|this page]] as a test page. And your sandbox solution seems to make sense. I'd thought the leaky div was something to do with the guess it must be something to do with the <code><nowiki><dl class="figure-n-counter-set-to-zero"></dl></nowiki></code>. It had seemed to work fine for images inserted in the default <code><nowiki>[[File.example.jpg|thumb|caption]]</nowiki></code> format, so I also tried to implement it into the <code><nowiki>{{fig|...}}</nowiki></code> (which can act as a multiple image holding template) for when a page is going to contain a mixture of <code><nowiki>[[file:...]]</nowiki></code> and <code><nowiki>{{fig|...}}</nowiki></code>. It seems your solution does what I was thinking without leaking the div though. Thanks again for looking into it. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 22:57, 10 February 2021 (UTC) == Stage-scripts.. == Over on English Wikisource I wrote some templates for formatting 'drama' scripts. Would it be possible to get an import of the Stagescript template family over here on Wikiversity? The reason is that I wanted to do a reformat on some material I wrote a while back. https://en.wikisource.org/wiki/Special:AllPages?from=Stagescript&to=&namespace=10 It's the templates at the top of the list. The way I wrote the template and styles, it should be straightforward to adapt for various script/screenplay formats, by writing appropriate style-sheets? [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 01:46, 4 March 2021 (UTC) :{{re|ShakespeareFan00}} That should be fine! I've imported those across now, so let me know if they look like they're working. Nice organisation of the template set. I would suggest also making a [[Template:Stagescript]] page as the main documentation page just so that there's a root page when people look. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:35, 4 March 2021 (UTC) ::If you want to start documenting feel free. Whilst my format isn't exactly the same as a production format, I've based some aspects of the model on the examples here ( essentially the screenplay and US Radio Drama formats)- https://www.bbc.co.uk/writersroom/resources/medium-and-format. If you know CSS , you can add formats closer to those examples. Also I am wondering if for Wikisource purposes we need a /slide template in addition to /sdr1 and /fx. The template fammily can then be used to develop 'presentational' scripts, as well as drama. [[User:ShakespeareFan00|ShakespeareFan00]] ([[User talk:ShakespeareFan00|discuss]] • [[Special:Contributions/ShakespeareFan00|contribs]]) 12:08, 5 March 2021 (UTC) == A Barnstar for you! == {{The Shootin Barnstar|color=Black|textcolor=I can see you are already doing well here. Keep going and happy editing. --[[User:IamTheAstronomer|IamTheAstronomer]] ([[User talk:IamTheAstronomer|discuss]] • [[Special:Contributions/IamTheAstronomer|contribs]]) 23:43, 21 March 2021 (UTC)}} == You have earned the Wikiversitian Award! == [[File:Wikiversity-logo.svg|thumb|left|124px]] May I present the Wikiversitian Award to this editor due to the fact that they have been an exceedingly outstanding contributor here. Believing they are an editor who has a huge level of competence, I decided to present this award to them for making Wikiversity the community it is meant to be. I wish this editor good luck with all their future endeavours. --[[User:IamTheAstronomer|IamTheAstronomer]] [[User talk:IamTheAstronomer|Talk]] 20:50, 30 March 2021 (UTC) == Copying links == Hi Thomas. Thanks for your help. I have copied the Wikipedia article to [[User:Dudley Miles/sandbox]] to work on it. I could easily create wikilinks by changing [[ to [[w:, but that leaves links as e.g. <nowiki>[[w:Mercia]]</nowiki>. Do I have to manually change every link to <nowiki>[[w:Mercia|Mercia]]</nowiki> or is there a way to automate this? [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 12:49, 27 September 2021 (UTC) :@[[User:Dudley Miles|Dudley Miles]]: Yes, you can change all the links in the page to point to wikipedia using: :* at the top of the section or page: <code><nowiki>{{subst:</nowiki>[[Template:Convert links|convert_links]]|</code> :* at the bottom of the section or page: <code><nowiki>}}</nowiki></code> :I've gone ahead and done so in your sandbox (after removing the <code>w:</code>currently present), so hopefully that worked, but let me know if any didn't link up correctly. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 00:04, 28 September 2021 (UTC) ::Many thanks for your help Thomas. ::Am I correct in thinking that [[Template:Sfn]] only partly implements [[w:Template:Sfn]]? In Wikipedia hovering over the reference number in the text gives you an option to go straight to the source, including opening a web page, but in Wikiversity I only seem to be able to go to the citation and then manually find the source. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 09:00, 28 September 2021 (UTC) :::@[[User:Dudley Miles|Dudley Miles]]: Hmm, check your [[Special:Preferences#mw-prefsection-gadgets|preferences]]. I think it's the '[[mw:Reference_Tooltips|reference tooltips]]' gadget that's enabled by default on WP but still available on WV. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 07:05, 29 September 2021 (UTC) I have been working out how to manage editing in Wikiversity. I cannot get tooltips to work in my sandbox on either of my computers. However, I am not sure what is going on as it seems to work on my mobile phone and works for my computers on preprints. I have also been bodging to get sfn working. It does not work correctly in Wikiversity with the cite encyclopedia template. I also find I need to use the harvid field in the sources for it to work correctly. In fact, it then works better than on Wikipedia. The great advantage of sfn used to be that it highlights reference errors and unused sources, but the latter function was removed on Wikipedia. Both functions still work on Wikiversity. Thanks. [[User:Dudley Miles|Dudley Miles]] ([[User talk:Dudley Miles|discuss]] • [[Special:Contributions/Dudley Miles|contribs]]) 14:00, 29 September 2021 (UTC) == How we will see unregistered users == <section begin=content/> Hi! You get this message because you are an admin on a Wikimedia wiki. When someone edits a Wikimedia wiki without being logged in today, we show their IP address. As you may already know, we will not be able to do this in the future. This is a decision by the Wikimedia Foundation Legal department, because norms and regulations for privacy online have changed. Instead of the IP we will show a masked identity. You as an admin '''will still be able to access the IP'''. There will also be a new user right for those who need to see the full IPs of unregistered users to fight vandalism, harassment and spam without being admins. Patrollers will also see part of the IP even without this user right. We are also working on [[m:IP Editing: Privacy Enhancement and Abuse Mitigation/Improving tools|better tools]] to help. If you have not seen it before, you can [[m:IP Editing: Privacy Enhancement and Abuse Mitigation|read more on Meta]]. If you want to make sure you don’t miss technical changes on the Wikimedia wikis, you can [[m:Global message delivery/Targets/Tech ambassadors|subscribe]] to [[m:Tech/News|the weekly technical newsletter]]. We have [[m:IP Editing: Privacy Enhancement and Abuse Mitigation#IP Masking Implementation Approaches (FAQ)|two suggested ways]] this identity could work. '''We would appreciate your feedback''' on which way you think would work best for you and your wiki, now and in the future. You can [[m:Talk:IP Editing: Privacy Enhancement and Abuse Mitigation|let us know on the talk page]]. You can write in your language. The suggestions were posted in October and we will decide after 17 January. Thank you. /[[m:User:Johan (WMF)|Johan (WMF)]]<section end=content/> 18:14, 4 January 2022 (UTC) <!-- Message sent by User:Johan (WMF)@metawiki using the list at https://meta.wikimedia.org/w/index.php?title=User:Johan_(WMF)/Target_lists/Admins2022(3)&oldid=22532499 --> ==question== Dr. Shafee I realize your busy, however I was wondering what the timetable might be for PDF [https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/The_Kivu_Ebola_Epidemic] its been about 1 month and a half since 13 April (I of course, know there are several articles you deal with from WikiJournal). I want to thank you for your very valuable time as always, Ozzie--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:05, 4 June 2022 (UTC) :@[[User:Ozzie10aaaa|Ozzie10aaaa]]: Thanks for flagging, and apologies for the delay. I'm in the process of training new users on how to do the off-wiki PDF formatting, so will use it as an example (as you've noticed, we have a bit of a backlog!). [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 04:20, 12 June 2022 (UTC) ::Dr Shafee, I completely understand and thank you as always, Ozzie--[[User:Ozzie10aaaa|Ozzie10aaaa]] ([[User talk:Ozzie10aaaa|discuss]] • [[Special:Contributions/Ozzie10aaaa|contribs]]) 12:28, 12 June 2022 (UTC) == Files Missing Information == Thanks for uploading files to Wikiversity. All files must have source and license information to stay at Wikiversity. The following files are missing {{tlx|Information}} and/or [[Wikiversity:License tags]], and will be deleted if the missing information is not added. See [[Wikiversity:Uploading files]] for more information. {{colbegin|3}} * [[:File:Ziats Table1.png]] * [[:File:Ziats)Figure 1.jpg]] {{colend}} [[User:MaintenanceBot|MaintenanceBot]] ([[User talk:MaintenanceBot|discuss]] • [[Special:Contributions/MaintenanceBot|contribs]]) 02:00, 23 June 2022 (UTC) == A number of backlogged WJS submissions == Hi Thomas, there are a few WJS submissions which listed you as the peer review coordinator. I was wondering what the status are for those submissions: # [[WikiJournal Preprints/Induced stem cells]] (no records of having peer reviews submitted) # [[WikiJournal Preprints/Moisture Content as a Proximate Factor in Nest Site Attractiveness for Temnothorax rugatulus]] (I will follow up with the author as he appears to be somewhat active on Wikipedia) # [[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] (authors need to respond to third reviewers' second-round of comments; pinging {{u|Kaexer}} to transclude [[Talk:WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats#Updated manuscript|updated PDF manuscript]] and {{u|Agan56}} to get ready for correspondence with this reviewer) If you have additional information for any of these submissions, please let me know. Thanks. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:52, 10 July 2022 (UTC) == File name error == Hi Thomas, one of the tech editor accidentally thought the authors' version was the accepted version and uploaded the file with that article's name with that assumption. Can you delete [[:File:Perspectives on the social license of the forest products.pdf]] since I can't rename/move the file to another name? [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 16:02, 15 July 2022 (UTC) :No problem. I've moved it to [[:File:Perspectives on the social license of the forest products - Author's response.pdf|File:Perspectives on the social license of the forest products - Author's response.pdf]] and deleted the redirect page left behind. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:07, 18 July 2022 (UTC) ::Thanks very much. [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 19:36, 18 July 2022 (UTC) == Continuing Email Discussion == Hello T. Shafee, I've sent you an email back in March regarding the [[WikiJournal Preprints/The Effect of Corticosteroids on the Mortality Rate in COVID-19 Patients, v2]] medical paper. I'm assuming you might've missed it, which isn't an issue! I can ask the questions here: * I wanted to get a confirmation that the topic is suitable for a medical paper. I see that there are similar studies on the internet in regards to this as recent as December 2021--just wanted to make sure my efforts are being put into a useful field. * Is it an obligation to mention the number of studies incorporated in the medical paper? EDIT: I also wanted to see if writing a [[WikiJournal of Humanities]] paper on meditation would be a perfect topic. I'm not sure if you're familiar with the guidelines for that book, but I figured it was worth asking. Thank you! —[[User:Atcovi|Atcovi]] [[User talk:Atcovi|(Talk]] - [[Special:Contributions/Atcovi|Contribs)]] 21:21, 20 July 2022 (UTC) 5ftg48b6itvhzqaai0q5gystw6qg9pw 2 219126 2408173 2407327 2022-07-20T12:35:55Z ThaniosAkro 2805358 /* Examples */ wikitext text/x-wiki <math>3</math> cube roots of <math>W</math> <math>W = 0.828 + 2.035\cdot i</math> <math>w_0 = 1.2 + 0.5\cdot i</math> <math>w_1 = \frac{-1.2 - 0.5\sqrt{3}}{2} + \frac{1.2\sqrt{3} - 0.5}{2}\cdot i</math> <math>w_2 = \frac{-1.2 + 0.5\sqrt{3}}{2} + \frac{- 1.2\sqrt{3} - 0.5}{2}\cdot i</math> <math>w_0^3 = w_1^3 = w_2^3 = W</math> <math></math> <math></math> <math>y = x^3 - x</math> <math>y = x^3</math> <math>y = x^3 + x</math> ===allEqual=== <math>y = f(x) = x^3</math> <math>y = f(-x)</math> <math>y = f(x) = x^3 + x</math> <math>x = p</math> <math>y = f(x) = (x-5)^3 - 4(x-5) + 7</math> {{Robelbox|title=[[Wikiversity:Welcome|Welcome]]|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em;"> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> ====Welcomee==== {{Robelbox|title=[[Wikiversity:Welcome|Welcome]]|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em; background-color: #FFF800; "> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> =====Welcomen===== {{Robelbox|title=|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em; background-color: #FFFFFF; "> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> {{Robelbox/close}} {{Robelbox/close}} {{Robelbox/close}} <noinclude> [[Category: main page templates]] </noinclude> ===text does not wrap=== <div>{{Wikiversity:Main Page/Introduction|theme={{{intro|13}}}}}</div> [[Wikiversity:Main Page/Introduction intro]] [[https://en.wikiversity.org/w/index.php?title=Wikiversity:Main_Page/Layout Layout]] [[https://en.wikiversity.org/w/index.php?title=Wikiversity:Main_Page/Introduction Introduction]] {{RoundBoxTop|theme=5}} {{Robelbox|title=|theme={{{theme|99}}}}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFFCF1;"> [[File:0715wrap01.png|thumb|400px|''' 2 screen shots showing where text wraps and where text doesn't wrap.''' ]] Hello professor Braunschweig, The 2 screenshots are of my sandbox. The left hand shot shows that text when displayed normally doesn't wrap. The right hand shot of preview taken in editing mode shows that text wraps. I prefer the right hand method of text automatically wrapping. How do I ensure this? Thanks. {{RoundBoxTop|theme=5}} {{Robelbox|title=|theme={{{theme|99}}}}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFF600;"> [[File:0715wrap01.png|thumb|400px|''' 2 screen shots showing where text wraps and where text doesn't wrap.''' ]] Hello professor Braunschweig, The 2 screenshots are of my sandbox. The left hand shot shows that text when displayed normally doesn't wrap. The right hand shot of preview taken in editing mode shows that text wraps. I prefer the right hand method of text automatically wrapping. How do I ensure this? Thanks. </div> {{Robelbox/close}} {{RoundBoxBottom}} </div> {{Robelbox/close}} {{RoundBoxBottom}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFFCF1;"> <syntaxhighlight lang=python> </syntaxhighlight> For function <code>oneRootOfCubic()</code> see [[Cubic_function#In_practice | Cubic_function: In_practice.]] </div> {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> {{RoundBoxBottom}} <math></math> <math></math> <math></math> ===Examples=== {{RoundBoxTop|theme=5}} <math></math> <math></math> <math></math> <math></math> <math>39x^2 + 64y^2 - 2496 = 0</math> <math>64x^2 + 39y^2 - 2496 = 0</math> <math></math> <math></math> <math></math> ====Techniques==== {{RoundBoxTop|theme=4}} =====For speed===== {{RoundBoxTop|theme=7}} ======Many comparisons====== {{RoundBoxTop|theme=8}} If your code contains many numerical comparisons, it may be tempting to put: <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. if a == b == c == d == e == f == g == h == 0 : pass </syntaxhighlight> If all values <code>a,b,c,d,e,f,g,h</code> are equal and non-zero, processing the above statement takes time. For greater speed, put <math>0</math> and the value most likely to be non-zero at beginning of comparison: <syntaxhighlight lang=python> # python code. if 0 == f == a == b == c == d == e == g == h : pass </syntaxhighlight> <math></math> <math></math> <math></math> <math></math> <math></math> {{RoundBoxBottom}} ======Divide by 2====== {{RoundBoxTop|theme=8}} <math></math> <math></math> <math></math> <math></math> Division by 2 seems simple enough: <syntaxhighlight lang=python> # python code. a = b / 2 </syntaxhighlight> Divisions are time consuming. If b is a large Decimal number, the following code is faster: <syntaxhighlight lang=python> # python code. a = D('0.5') * b </syntaxhighlight> If b is <code>type int,</code> right shift is faster than multiplication by <code>0.5:</code> <syntaxhighlight lang=python> # python code. a = b >> 1 </syntaxhighlight> Also, right shift preserves precision of <code>type int:</code> <syntaxhighlight lang=python> # python code. >>> b = 12345678901234567890123456789 >>> a = b/2 ; a 6.172839450617284e+27 >>> a = b >> 1 ; a 6172839450617283945061728394 </syntaxhighlight> {{RoundBoxTop|theme=8}} To preserve rightmost bit: <syntaxhighlight lang=python> # python code. >>> b = 12345678901234567890123456789 >>> rightbit = b & 1 ; rightbit 1 >>> b >>= 1 ; b 6172839450617283945061728394 </syntaxhighlight> <math></math> <math></math> <math></math> <math></math> <math></math> {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} ======For clarity====== {{RoundBoxTop|theme=7}} <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> <math></math> <math></math> {{RoundBoxBottom}} <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> <math></math> <math></math> {{RoundBoxBottom}} {{RoundBoxBottom}} ===tables=== {{RoundBoxTop|theme=1}} {| class="wikitable" |- ! || No equal roots !! 2 equal roots !! 3 equal roots !! 4 equal roots !! 2 pairs of equal roots |- | Cubic: 1(a), 2(a) | different | different | different | same | different |- | Quadratic: 1(b), 2(b) | different | different | same, 1root | null | same, 2roots |- | Linear: 1(c), 2(c) | different | same | null | null | null |} See [[Cubic_function#Function_as_product_of_linear_function_and_quadratic | Function_as_product_of_linear_function_and_quadratic]] above. To calculate all roots: <syntaxhighlight lang=python> # python code. a,b,c,d = 1,-3,-9,-5 # Associated quadratic: p = -1 A = a B = A*p + b C = B*p + c # Associated linear function: a1 = A b1 = a1*p + B print ('x3 =', -b1/a1) </syntaxhighlight> <syntaxhighlight> x3 = 5.0 </syntaxhighlight> Roots of cubic function <math>f(x) = x^3 - 3x^2 - 9x - 5</math> are <math>-1, -1, 5.</math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> {{RoundBoxBottom}} =Testing= {{RoundBoxTop|theme=2}} [[File:0410cubic01.png|thumb|400px|''' Graph of cubic function with coefficient a negative.''' </br> There is no absolute maximum or absolute minimum. ]] Coefficient <math>a</math> may be negative as shown in diagram. As <math>abs(x)</math> increases, the value of <math>f(x)</math> is dominated by the term <math>-ax^3.</math> When <math>x</math> has a very large negative value, <math>f(x)</math> is always positive. When <math>x</math> has a very large positive value, <math>f(x)</math> is always negative. Unless stated otherwise, any reference to "cubic function" on this page will assume coefficient <math>a</math> positive. {{RoundBoxBottom}} <math>x_{poi} = -1</math> <math></math> <math></math> <math></math> <math></math> =====Various planes in 3 dimensions===== {{RoundBoxTop|theme=2}} <gallery> File:0713x=4.png|<small>plane x=4.</small> File:0713y=3.png|<small>plane y=3.</small> File:0713z=-2.png|<small>plane z=-2.</small> </gallery> {{RoundBoxBottom}} <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> <syntaxhighlight> 1.4142135623730950488016887242096980785696718753769480731766797379907324784621070388503875343276415727 3501384623091229702492483605585073721264412149709993583141322266592750559275579995050115278206057147 0109559971605970274534596862014728517418640889198609552329230484308714321450839762603627995251407989 6872533965463318088296406206152583523950547457502877599617298355752203375318570113543746034084988471 6038689997069900481503054402779031645424782306849293691862158057846311159666871301301561856898723723 5288509264861249497715421833420428568606014682472077143585487415565706967765372022648544701585880162 0758474922657226002085584466521458398893944370926591800311388246468157082630100594858704003186480342 1948972782906410450726368813137398552561173220402450912277002269411275736272804957381089675040183698 6836845072579936472906076299694138047565482372899718032680247442062926912485905218100445984215059112 0249441341728531478105803603371077309182869314710171111683916581726889419758716582152128229518488472 </syntaxhighlight> <math>\theta_1</math> {{RoundBoxTop|theme=2}} [[File:0422xx_x_2.png|thumb|400px|''' Figure 1: Diagram illustrating relationship between <math>f(x) = x^2 - x - 2</math> and <math>f'(x) = 2x - 1.</math>''' </br> ]] {{RoundBoxBottom}} <math>O\ (0,0,0)</math> <math>M\ (A_1,B_1,C_1)</math> <math>N\ (A_2,B_2,C_2)</math> <math>\theta</math> <math>\ \ \ \ \ \ \ \ </math> :<math>\begin{align} (6) - (7),\ 4Apq + 2Bq =&\ 0\\ 2Ap + B =&\ 0\\ 2Ap =&\ - B\\ \\ p =&\ \frac{-B}{2A}\ \dots\ (8) \end{align}</math> <math>\ \ \ \ \ \ \ \ </math> :<math>\begin{align} 1.&4141475869yugh\\ &2645er3423231sgdtrf\\ &dhcgfyrt45erwesd \end{align}</math> <math>\ \ \ \ \ \ \ \ </math> :<math> 4\sin 18^\circ = \sqrt{2(3 - \sqrt 5)} = \sqrt 5 - 1 </math> ====Introduction to floats==== {{RoundBoxTop|theme=5}} Although integers are great for many situations, they have a serious limitation, integers are [[Wikipedia:Natural number|whole numbers]]. This means that they do not include all [[Wikipedia:Real number|real numbers]]. A ''real number'' is a value that represents a quantity along a continuous line<ref>[[Wikipedia:Real number]]</ref>, which means that it can have fractions in decimal forms. <code>4.5</code>, <code>1.25</code>, and <code>0.75</code> are all real numbers. In computer science, real numbers are represented as floats. To test if a number is float, we can use the <code>isinstance</code> built-in function. <syntaxhighlight lang=python> >>> isinstance(4.5, float) True >>> isinstance(1.25, float) True >>> isinstance(0.75, float) True >>> isinstance(3.14159, float) True >>> isinstance(2.71828, float) True >>> isinstance(1.0, float) True >>> isinstance(271828, float) False >>> isinstance(0, float) False >>> isinstance(0.0, float) True </syntaxhighlight> As a general rule of thumb, floats have a ''[[Wikipedia:Decimal mark|decimal point]]'' and integers do not have a ''decimal point''. So even though <code>4</code> and <code>4.0</code> are the same number, <code>4</code> is an integer while <code>4.0</code> is a float. The basic arithmetic operations used for integers will also work for floats. (Bitwise operators will not work with floats.) <syntaxhighlight lang=python> >>> 4.0 + 2.0 6.0 >>> -1.0 + 4.5 3.5 >>> 1.75 - 1.5 0.25 >>> 4.13 - 1.1 3.03 >>> 4.5 // 1.0 4.0 >>> 4.5 / 1.0 4.5 >>> 4.5 % 1.0 0.5 >>> 7.75 * 0.25 1.9375 >>> 0.5 * 0.5 0.25 >>> 1.5 ** 2.0 2.25 </syntaxhighlight> {{RoundBoxBottom}} rb6wokcsuvfyao9a51bmcgxjrzn727v 2408174 2408173 2022-07-20T12:37:04Z ThaniosAkro 2805358 /* For clarity */ wikitext text/x-wiki <math>3</math> cube roots of <math>W</math> <math>W = 0.828 + 2.035\cdot i</math> <math>w_0 = 1.2 + 0.5\cdot i</math> <math>w_1 = \frac{-1.2 - 0.5\sqrt{3}}{2} + \frac{1.2\sqrt{3} - 0.5}{2}\cdot i</math> <math>w_2 = \frac{-1.2 + 0.5\sqrt{3}}{2} + \frac{- 1.2\sqrt{3} - 0.5}{2}\cdot i</math> <math>w_0^3 = w_1^3 = w_2^3 = W</math> <math></math> <math></math> <math>y = x^3 - x</math> <math>y = x^3</math> <math>y = x^3 + x</math> ===allEqual=== <math>y = f(x) = x^3</math> <math>y = f(-x)</math> <math>y = f(x) = x^3 + x</math> <math>x = p</math> <math>y = f(x) = (x-5)^3 - 4(x-5) + 7</math> {{Robelbox|title=[[Wikiversity:Welcome|Welcome]]|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em;"> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> ====Welcomee==== {{Robelbox|title=[[Wikiversity:Welcome|Welcome]]|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em; background-color: #FFF800; "> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> =====Welcomen===== {{Robelbox|title=|theme={{{theme|9}}}}} <div style="padding-top:0.25em; padding-bottom:0.2em; padding-left:0.5em; padding-right:0.75em; background-color: #FFFFFF; "> [[Wikiversity:Welcome|Wikiversity]] is a [[Wikiversity:Sister projects|Wikimedia Foundation]] project devoted to [[learning resource]]s, [[learning projects]], and [[Portal:Research|research]] for use in all [[:Category:Resources by level|levels]], types, and styles of education from pre-school to university, including professional training and informal learning. We invite [[Wikiversity:Wikiversity teachers|teachers]], [[Wikiversity:Learning goals|students]], and [[Portal:Research|researchers]] to join us in creating [[open educational resources]] and collaborative [[Wikiversity:Learning community|learning communities]]. To learn more about Wikiversity, try a [[Help:Guides|guided tour]], learn about [[Wikiversity:Adding content|adding content]], or [[Wikiversity:Introduction|start editing now]]. </div> {{Robelbox/close}} {{Robelbox/close}} {{Robelbox/close}} <noinclude> [[Category: main page templates]] </noinclude> ===text does not wrap=== <div>{{Wikiversity:Main Page/Introduction|theme={{{intro|13}}}}}</div> [[Wikiversity:Main Page/Introduction intro]] [[https://en.wikiversity.org/w/index.php?title=Wikiversity:Main_Page/Layout Layout]] [[https://en.wikiversity.org/w/index.php?title=Wikiversity:Main_Page/Introduction Introduction]] {{RoundBoxTop|theme=5}} {{Robelbox|title=|theme={{{theme|99}}}}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFFCF1;"> [[File:0715wrap01.png|thumb|400px|''' 2 screen shots showing where text wraps and where text doesn't wrap.''' ]] Hello professor Braunschweig, The 2 screenshots are of my sandbox. The left hand shot shows that text when displayed normally doesn't wrap. The right hand shot of preview taken in editing mode shows that text wraps. I prefer the right hand method of text automatically wrapping. How do I ensure this? Thanks. {{RoundBoxTop|theme=5}} {{Robelbox|title=|theme={{{theme|99}}}}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFF600;"> [[File:0715wrap01.png|thumb|400px|''' 2 screen shots showing where text wraps and where text doesn't wrap.''' ]] Hello professor Braunschweig, The 2 screenshots are of my sandbox. The left hand shot shows that text when displayed normally doesn't wrap. The right hand shot of preview taken in editing mode shows that text wraps. I prefer the right hand method of text automatically wrapping. How do I ensure this? Thanks. </div> {{Robelbox/close}} {{RoundBoxBottom}} </div> {{Robelbox/close}} {{RoundBoxBottom}} <div style="flex: 10%; min-width: 10em; vertical-align: top; background-color: #FFFCF1;"> <syntaxhighlight lang=python> </syntaxhighlight> For function <code>oneRootOfCubic()</code> see [[Cubic_function#In_practice | Cubic_function: In_practice.]] </div> {{RoundBoxTop|theme=2}} <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> {{RoundBoxBottom}} <math></math> <math></math> <math></math> ===Examples=== {{RoundBoxTop|theme=5}} <math></math> <math></math> <math></math> <math></math> <math>39x^2 + 64y^2 - 2496 = 0</math> <math>64x^2 + 39y^2 - 2496 = 0</math> <math></math> <math></math> <math></math> ====Techniques==== {{RoundBoxTop|theme=4}} =====For speed===== {{RoundBoxTop|theme=7}} ======Many comparisons====== {{RoundBoxTop|theme=8}} If your code contains many numerical comparisons, it may be tempting to put: <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. if a == b == c == d == e == f == g == h == 0 : pass </syntaxhighlight> If all values <code>a,b,c,d,e,f,g,h</code> are equal and non-zero, processing the above statement takes time. For greater speed, put <math>0</math> and the value most likely to be non-zero at beginning of comparison: <syntaxhighlight lang=python> # python code. if 0 == f == a == b == c == d == e == g == h : pass </syntaxhighlight> <math></math> <math></math> <math></math> <math></math> <math></math> {{RoundBoxBottom}} ======Divide by 2====== {{RoundBoxTop|theme=8}} <math></math> <math></math> <math></math> <math></math> Division by 2 seems simple enough: <syntaxhighlight lang=python> # python code. a = b / 2 </syntaxhighlight> Divisions are time consuming. If b is a large Decimal number, the following code is faster: <syntaxhighlight lang=python> # python code. a = D('0.5') * b </syntaxhighlight> If b is <code>type int,</code> right shift is faster than multiplication by <code>0.5:</code> <syntaxhighlight lang=python> # python code. a = b >> 1 </syntaxhighlight> Also, right shift preserves precision of <code>type int:</code> <syntaxhighlight lang=python> # python code. >>> b = 12345678901234567890123456789 >>> a = b/2 ; a 6.172839450617284e+27 >>> a = b >> 1 ; a 6172839450617283945061728394 </syntaxhighlight> {{RoundBoxTop|theme=8}} To preserve rightmost bit: <syntaxhighlight lang=python> # python code. >>> b = 12345678901234567890123456789 >>> rightbit = b & 1 ; rightbit 1 >>> b >>= 1 ; b 6172839450617283945061728394 </syntaxhighlight> <math></math> <math></math> <math></math> <math></math> <math></math> {{RoundBoxBottom}} {{RoundBoxBottom}} {{RoundBoxBottom}} =====For clarity===== {{RoundBoxTop|theme=7}} <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> <math></math> <math></math> {{RoundBoxBottom}} <math></math> <math></math> <math></math> <math></math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> <math></math> <math></math> {{RoundBoxBottom}} {{RoundBoxBottom}} ===tables=== {{RoundBoxTop|theme=1}} {| class="wikitable" |- ! || No equal roots !! 2 equal roots !! 3 equal roots !! 4 equal roots !! 2 pairs of equal roots |- | Cubic: 1(a), 2(a) | different | different | different | same | different |- | Quadratic: 1(b), 2(b) | different | different | same, 1root | null | same, 2roots |- | Linear: 1(c), 2(c) | different | same | null | null | null |} See [[Cubic_function#Function_as_product_of_linear_function_and_quadratic | Function_as_product_of_linear_function_and_quadratic]] above. To calculate all roots: <syntaxhighlight lang=python> # python code. a,b,c,d = 1,-3,-9,-5 # Associated quadratic: p = -1 A = a B = A*p + b C = B*p + c # Associated linear function: a1 = A b1 = a1*p + B print ('x3 =', -b1/a1) </syntaxhighlight> <syntaxhighlight> x3 = 5.0 </syntaxhighlight> Roots of cubic function <math>f(x) = x^3 - 3x^2 - 9x - 5</math> are <math>-1, -1, 5.</math> <syntaxhighlight lang=python> # python code. </syntaxhighlight> {{RoundBoxBottom}} =Testing= {{RoundBoxTop|theme=2}} [[File:0410cubic01.png|thumb|400px|''' Graph of cubic function with coefficient a negative.''' </br> There is no absolute maximum or absolute minimum. ]] Coefficient <math>a</math> may be negative as shown in diagram. As <math>abs(x)</math> increases, the value of <math>f(x)</math> is dominated by the term <math>-ax^3.</math> When <math>x</math> has a very large negative value, <math>f(x)</math> is always positive. When <math>x</math> has a very large positive value, <math>f(x)</math> is always negative. Unless stated otherwise, any reference to "cubic function" on this page will assume coefficient <math>a</math> positive. {{RoundBoxBottom}} <math>x_{poi} = -1</math> <math></math> <math></math> <math></math> <math></math> =====Various planes in 3 dimensions===== {{RoundBoxTop|theme=2}} <gallery> File:0713x=4.png|<small>plane x=4.</small> File:0713y=3.png|<small>plane y=3.</small> File:0713z=-2.png|<small>plane z=-2.</small> </gallery> {{RoundBoxBottom}} <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> <syntaxhighlight lang=python> </syntaxhighlight> <syntaxhighlight> </syntaxhighlight> <syntaxhighlight> 1.4142135623730950488016887242096980785696718753769480731766797379907324784621070388503875343276415727 3501384623091229702492483605585073721264412149709993583141322266592750559275579995050115278206057147 0109559971605970274534596862014728517418640889198609552329230484308714321450839762603627995251407989 6872533965463318088296406206152583523950547457502877599617298355752203375318570113543746034084988471 6038689997069900481503054402779031645424782306849293691862158057846311159666871301301561856898723723 5288509264861249497715421833420428568606014682472077143585487415565706967765372022648544701585880162 0758474922657226002085584466521458398893944370926591800311388246468157082630100594858704003186480342 1948972782906410450726368813137398552561173220402450912277002269411275736272804957381089675040183698 6836845072579936472906076299694138047565482372899718032680247442062926912485905218100445984215059112 0249441341728531478105803603371077309182869314710171111683916581726889419758716582152128229518488472 </syntaxhighlight> <math>\theta_1</math> {{RoundBoxTop|theme=2}} [[File:0422xx_x_2.png|thumb|400px|''' Figure 1: Diagram illustrating relationship between <math>f(x) = x^2 - x - 2</math> and <math>f'(x) = 2x - 1.</math>''' </br> ]] {{RoundBoxBottom}} <math>O\ (0,0,0)</math> <math>M\ (A_1,B_1,C_1)</math> <math>N\ (A_2,B_2,C_2)</math> <math>\theta</math> <math>\ \ \ \ \ \ \ \ </math> :<math>\begin{align} (6) - (7),\ 4Apq + 2Bq =&\ 0\\ 2Ap + B =&\ 0\\ 2Ap =&\ - B\\ \\ p =&\ \frac{-B}{2A}\ \dots\ (8) \end{align}</math> <math>\ \ \ \ \ \ \ \ </math> :<math>\begin{align} 1.&4141475869yugh\\ &2645er3423231sgdtrf\\ &dhcgfyrt45erwesd \end{align}</math> <math>\ \ \ \ \ \ \ \ </math> :<math> 4\sin 18^\circ = \sqrt{2(3 - \sqrt 5)} = \sqrt 5 - 1 </math> ====Introduction to floats==== {{RoundBoxTop|theme=5}} Although integers are great for many situations, they have a serious limitation, integers are [[Wikipedia:Natural number|whole numbers]]. This means that they do not include all [[Wikipedia:Real number|real numbers]]. A ''real number'' is a value that represents a quantity along a continuous line<ref>[[Wikipedia:Real number]]</ref>, which means that it can have fractions in decimal forms. <code>4.5</code>, <code>1.25</code>, and <code>0.75</code> are all real numbers. In computer science, real numbers are represented as floats. To test if a number is float, we can use the <code>isinstance</code> built-in function. <syntaxhighlight lang=python> >>> isinstance(4.5, float) True >>> isinstance(1.25, float) True >>> isinstance(0.75, float) True >>> isinstance(3.14159, float) True >>> isinstance(2.71828, float) True >>> isinstance(1.0, float) True >>> isinstance(271828, float) False >>> isinstance(0, float) False >>> isinstance(0.0, float) True </syntaxhighlight> As a general rule of thumb, floats have a ''[[Wikipedia:Decimal mark|decimal point]]'' and integers do not have a ''decimal point''. So even though <code>4</code> and <code>4.0</code> are the same number, <code>4</code> is an integer while <code>4.0</code> is a float. The basic arithmetic operations used for integers will also work for floats. (Bitwise operators will not work with floats.) <syntaxhighlight lang=python> >>> 4.0 + 2.0 6.0 >>> -1.0 + 4.5 3.5 >>> 1.75 - 1.5 0.25 >>> 4.13 - 1.1 3.03 >>> 4.5 // 1.0 4.0 >>> 4.5 / 1.0 4.5 >>> 4.5 % 1.0 0.5 >>> 7.75 * 0.25 1.9375 >>> 0.5 * 0.5 0.25 >>> 1.5 ** 2.0 2.25 </syntaxhighlight> {{RoundBoxBottom}} eqbp0uudwv6dsouzw0ggoukbdqtsc54 0 232983 2408188 2406547 2022-07-20T16:29:25Z Maddiegray11 2936309 /* Base rates of BD in different clinical settings and populations */ Moved a citation wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1996.03540040037030|journal=JAMA: The Journal of the American Medical Association|language=en|volume=276|issue=4|pages=293|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref><ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States |[https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285 Community Epidemiological Samples]<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States |[http://vb3lk7eb4t.search.serialssolutions.com/?ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Bipolar+Disorders+in+a+Community+Sample+of+Older+Adolescents%3A+Prevalence%2C+Phenomenology%2C+Comorbidity%2C+and+Course&rft.jtitle=Journal+of+the+American+Academy+of+Child+%26+Adolescent+Psychiatry&rft.au=LEWINSOHN%2C+PETER+M&rft.au=KLEIN%2C+DANIEL+N&rft.au=SEELEY%2C+JOHN+R&rft.date=1995&rft.pub=Elsevier+Inc&rft.issn=0890-8567&rft.eissn=1527-5418&rft.volume=34&rft.issue=4&rft.spage=454&rft.epage=463&rft_id=info:doi/10.1097%2F00004583-199504000-00012&rft.externalDocID=doi_10_1097_00004583_199504000_00012 Community samples (older adolescents)]<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |1% |K-SADS Semi-Structured Interview |- |United States |US National Epidemiological Catchment Area (ECA) database<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States |US National Comorbidity Survey (NCS)<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries |Community sample<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia |Community Samples<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States |Outpatient Clinic Sample<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |9.8% |Review of medical records, questionnaire data |- |United States |Outpatient Clinic Sample<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|date=2005|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' !Clinical Generalizability |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical | |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical | |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical | |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. === More on high preforming bipolar screening measures === {{collapse top| Expand for more information}} <big>'''7 Up 7 Down Inventory (7U7D)'''</big> * The 7 Up 7 Down Inventory is a recently developed and validated questionnaire with 14 items of manic and depressive tendencies carved from the General Behavior Inventory, a well-validated but cumbersome interview. For both mania and depression factors, 7 items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult)<ref name=":2">{{Cite journal|last=Youngstrom|first=Eric A.|last2=Murray|first2=Greg|last3=Johnson|first3=Sheri L.|last4=Findling|first4=Robert L.|date=2013-12|title=The 7 Up 7 Down Inventory: A 14-item measure of manic and depressive tendencies carved from the General Behavior Inventory|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970320/|journal=Psychological assessment|volume=25|issue=4|pages=1377–1383|doi=10.1037/a0033975|issn=1040-3590|pmc=PMC3970320|pmid=23914960}}</ref>.[https://en.wikiversity.org/wiki/OToPS/Measures/7_Up_7_Down_Inventory The 7 Up 7 Down Inventory, along with the accompanying research article can be found here] <big>'''Bipolar Spectrum Diagnostic Scale (BSDS)'''</big> *The Bipolar Spectrum Diagnostic Scale (BSDS) is a diagnostic tools that can assess for bipolar disorder in those who have Bipolar Disorder I, Bipolar Disorder II and Bipolar Disorder NOS. It was designed to help detect milder versions of bipolar disorder<ref name=":1">Zimmerman, M., Galione, J. N., Chelminski, I., Young, D. and Ruggero, C. J. (2010), Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. Bipolar Disorders, 12: 528–538. doi:10.1111/j.1399-5618.2010.00840.x</ref>. It is a self-report measure, and it has been shown to be generally effective in detecting bipolar disorder, though this effectiveness is not shown in individuals who have low insight.<ref name=":0">{{Cite journal|last=Nassir Ghaemi|first=S.|last2=Miller|first2=Christopher J.|last3=Berv|first3=Douglas A.|last4=Klugman|first4=Jeffry|last5=Rosenquist|first5=Klara J.|last6=Pies|first6=Ronald W.|date=February 2005|title=Sensitivity and specificity of a new bipolar spectrum diagnostic scale|url=https://www.ncbi.nlm.nih.gov/pubmed/15708426|journal=Journal of Affective Disorders|volume=84|issue=2-3|pages=273–277|doi=10.1016/S0165-0327(03)00196-4|issn=0165-0327|pmid=15708426}}</ref> The sensitivity of the BSDS is due to its focus on energy and drive rather than the mood symptoms present during hypomanic symptoms<ref name=":0" />. The threshold for a positive diagnosis is 13 points. The BSDS effectively screened out unipolar patients, maintained good sensitivity across the bipolar spectrum and low rate of false positives.<ref name=":0" />. <big>'''Mood Disorder Questionnaire (MDQ)'''</big> *The Mood Disorder Questionnaire (MDQ) is a self-report scale for bipolar disorder which focuses more on mood symptoms.<ref>Hirschfield, R., Williams, J., Spitzer R., Calabrese, J., Flynn L., Keck, P., Lewis L., McElroy S., Post, R., Rapport, D., Russel, J., Sachs, G., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. Am. J. Psychiatry 157, 1873-1875.</ref> It is very effective in detecting bipolar I disorder but less sensitive at detecting bipolar II disorder and Not Otherwise Specified (NOS).<ref>Miller, C., Ghaemi, S.N., Klugman, J., Berv, D.A., Pies, R.W., 2002. Utility of mood disorder questionnaire and bipolar spectrum diagnostic scale (Abstract). American Psychological Association Annual Meeting, Philadelphia, PA.</ref> {{collapse bottom}} === Interpreting adult bipolar disorder screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] * Also see the page on [[wikipedia:Likelihood_ratios_in_diagnostic_testing|likelihood ratios in diagnostic testing]] for more information ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="10" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} 975dd50nzdona3zcqbw4rk6rc9dx9pt 2408189 2408188 2022-07-20T16:30:19Z Maddiegray11 2936309 /* Base rates of BD in different clinical settings and populations */ deleted a citation wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States |[https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285 Community Epidemiological Samples]<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States |[http://vb3lk7eb4t.search.serialssolutions.com/?ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Bipolar+Disorders+in+a+Community+Sample+of+Older+Adolescents%3A+Prevalence%2C+Phenomenology%2C+Comorbidity%2C+and+Course&rft.jtitle=Journal+of+the+American+Academy+of+Child+%26+Adolescent+Psychiatry&rft.au=LEWINSOHN%2C+PETER+M&rft.au=KLEIN%2C+DANIEL+N&rft.au=SEELEY%2C+JOHN+R&rft.date=1995&rft.pub=Elsevier+Inc&rft.issn=0890-8567&rft.eissn=1527-5418&rft.volume=34&rft.issue=4&rft.spage=454&rft.epage=463&rft_id=info:doi/10.1097%2F00004583-199504000-00012&rft.externalDocID=doi_10_1097_00004583_199504000_00012 Community samples (older adolescents)]<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |1% |K-SADS Semi-Structured Interview |- |United States |US National Epidemiological Catchment Area (ECA) database<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States |US National Comorbidity Survey (NCS)<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries |Community sample<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia |Community Samples<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States |Outpatient Clinic Sample<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |9.8% |Review of medical records, questionnaire data |- |United States |Outpatient Clinic Sample<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|date=2005|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' !Clinical Generalizability |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical | |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical | |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical | |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. === More on high preforming bipolar screening measures === {{collapse top| Expand for more information}} <big>'''7 Up 7 Down Inventory (7U7D)'''</big> * The 7 Up 7 Down Inventory is a recently developed and validated questionnaire with 14 items of manic and depressive tendencies carved from the General Behavior Inventory, a well-validated but cumbersome interview. For both mania and depression factors, 7 items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult)<ref name=":2">{{Cite journal|last=Youngstrom|first=Eric A.|last2=Murray|first2=Greg|last3=Johnson|first3=Sheri L.|last4=Findling|first4=Robert L.|date=2013-12|title=The 7 Up 7 Down Inventory: A 14-item measure of manic and depressive tendencies carved from the General Behavior Inventory|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970320/|journal=Psychological assessment|volume=25|issue=4|pages=1377–1383|doi=10.1037/a0033975|issn=1040-3590|pmc=PMC3970320|pmid=23914960}}</ref>.[https://en.wikiversity.org/wiki/OToPS/Measures/7_Up_7_Down_Inventory The 7 Up 7 Down Inventory, along with the accompanying research article can be found here] <big>'''Bipolar Spectrum Diagnostic Scale (BSDS)'''</big> *The Bipolar Spectrum Diagnostic Scale (BSDS) is a diagnostic tools that can assess for bipolar disorder in those who have Bipolar Disorder I, Bipolar Disorder II and Bipolar Disorder NOS. It was designed to help detect milder versions of bipolar disorder<ref name=":1">Zimmerman, M., Galione, J. N., Chelminski, I., Young, D. and Ruggero, C. J. (2010), Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. Bipolar Disorders, 12: 528–538. doi:10.1111/j.1399-5618.2010.00840.x</ref>. It is a self-report measure, and it has been shown to be generally effective in detecting bipolar disorder, though this effectiveness is not shown in individuals who have low insight.<ref name=":0">{{Cite journal|last=Nassir Ghaemi|first=S.|last2=Miller|first2=Christopher J.|last3=Berv|first3=Douglas A.|last4=Klugman|first4=Jeffry|last5=Rosenquist|first5=Klara J.|last6=Pies|first6=Ronald W.|date=February 2005|title=Sensitivity and specificity of a new bipolar spectrum diagnostic scale|url=https://www.ncbi.nlm.nih.gov/pubmed/15708426|journal=Journal of Affective Disorders|volume=84|issue=2-3|pages=273–277|doi=10.1016/S0165-0327(03)00196-4|issn=0165-0327|pmid=15708426}}</ref> The sensitivity of the BSDS is due to its focus on energy and drive rather than the mood symptoms present during hypomanic symptoms<ref name=":0" />. The threshold for a positive diagnosis is 13 points. The BSDS effectively screened out unipolar patients, maintained good sensitivity across the bipolar spectrum and low rate of false positives.<ref name=":0" />. <big>'''Mood Disorder Questionnaire (MDQ)'''</big> *The Mood Disorder Questionnaire (MDQ) is a self-report scale for bipolar disorder which focuses more on mood symptoms.<ref>Hirschfield, R., Williams, J., Spitzer R., Calabrese, J., Flynn L., Keck, P., Lewis L., McElroy S., Post, R., Rapport, D., Russel, J., Sachs, G., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. Am. J. Psychiatry 157, 1873-1875.</ref> It is very effective in detecting bipolar I disorder but less sensitive at detecting bipolar II disorder and Not Otherwise Specified (NOS).<ref>Miller, C., Ghaemi, S.N., Klugman, J., Berv, D.A., Pies, R.W., 2002. Utility of mood disorder questionnaire and bipolar spectrum diagnostic scale (Abstract). American Psychological Association Annual Meeting, Philadelphia, PA.</ref> {{collapse bottom}} === Interpreting adult bipolar disorder screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] * Also see the page on [[wikipedia:Likelihood_ratios_in_diagnostic_testing|likelihood ratios in diagnostic testing]] for more information ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="10" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} 4juqlt1kcrzv00eaqle2cftu3p8lb14 2408190 2408189 2022-07-20T16:34:18Z Maddiegray11 2936309 /* Base rates of BD in different clinical settings and populations */ Moved all citations to the first column wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' !Clinical Generalizability |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical | |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical | |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical | |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. === More on high preforming bipolar screening measures === {{collapse top| Expand for more information}} <big>'''7 Up 7 Down Inventory (7U7D)'''</big> * The 7 Up 7 Down Inventory is a recently developed and validated questionnaire with 14 items of manic and depressive tendencies carved from the General Behavior Inventory, a well-validated but cumbersome interview. For both mania and depression factors, 7 items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult)<ref name=":2">{{Cite journal|last=Youngstrom|first=Eric A.|last2=Murray|first2=Greg|last3=Johnson|first3=Sheri L.|last4=Findling|first4=Robert L.|date=2013-12|title=The 7 Up 7 Down Inventory: A 14-item measure of manic and depressive tendencies carved from the General Behavior Inventory|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970320/|journal=Psychological assessment|volume=25|issue=4|pages=1377–1383|doi=10.1037/a0033975|issn=1040-3590|pmc=PMC3970320|pmid=23914960}}</ref>.[https://en.wikiversity.org/wiki/OToPS/Measures/7_Up_7_Down_Inventory The 7 Up 7 Down Inventory, along with the accompanying research article can be found here] <big>'''Bipolar Spectrum Diagnostic Scale (BSDS)'''</big> *The Bipolar Spectrum Diagnostic Scale (BSDS) is a diagnostic tools that can assess for bipolar disorder in those who have Bipolar Disorder I, Bipolar Disorder II and Bipolar Disorder NOS. It was designed to help detect milder versions of bipolar disorder<ref name=":1">Zimmerman, M., Galione, J. N., Chelminski, I., Young, D. and Ruggero, C. J. (2010), Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. Bipolar Disorders, 12: 528–538. doi:10.1111/j.1399-5618.2010.00840.x</ref>. It is a self-report measure, and it has been shown to be generally effective in detecting bipolar disorder, though this effectiveness is not shown in individuals who have low insight.<ref name=":0">{{Cite journal|last=Nassir Ghaemi|first=S.|last2=Miller|first2=Christopher J.|last3=Berv|first3=Douglas A.|last4=Klugman|first4=Jeffry|last5=Rosenquist|first5=Klara J.|last6=Pies|first6=Ronald W.|date=February 2005|title=Sensitivity and specificity of a new bipolar spectrum diagnostic scale|url=https://www.ncbi.nlm.nih.gov/pubmed/15708426|journal=Journal of Affective Disorders|volume=84|issue=2-3|pages=273–277|doi=10.1016/S0165-0327(03)00196-4|issn=0165-0327|pmid=15708426}}</ref> The sensitivity of the BSDS is due to its focus on energy and drive rather than the mood symptoms present during hypomanic symptoms<ref name=":0" />. The threshold for a positive diagnosis is 13 points. The BSDS effectively screened out unipolar patients, maintained good sensitivity across the bipolar spectrum and low rate of false positives.<ref name=":0" />. <big>'''Mood Disorder Questionnaire (MDQ)'''</big> *The Mood Disorder Questionnaire (MDQ) is a self-report scale for bipolar disorder which focuses more on mood symptoms.<ref>Hirschfield, R., Williams, J., Spitzer R., Calabrese, J., Flynn L., Keck, P., Lewis L., McElroy S., Post, R., Rapport, D., Russel, J., Sachs, G., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. Am. J. Psychiatry 157, 1873-1875.</ref> It is very effective in detecting bipolar I disorder but less sensitive at detecting bipolar II disorder and Not Otherwise Specified (NOS).<ref>Miller, C., Ghaemi, S.N., Klugman, J., Berv, D.A., Pies, R.W., 2002. Utility of mood disorder questionnaire and bipolar spectrum diagnostic scale (Abstract). American Psychological Association Annual Meeting, Philadelphia, PA.</ref> {{collapse bottom}} === Interpreting adult bipolar disorder screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] * Also see the page on [[wikipedia:Likelihood_ratios_in_diagnostic_testing|likelihood ratios in diagnostic testing]] for more information ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="10" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} gmz1zcthjepibhmzitkc6ofw1i4xg48 2408193 2408190 2022-07-20T17:04:24Z Maddiegray11 2936309 /* Gold standard diagnostic interviews */ Inserted names of diagnostic interviews and deleted extra columns wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' !Clinical Generalizability |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical | |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical | |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical | |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. === More on high preforming bipolar screening measures === {{collapse top| Expand for more information}} <big>'''7 Up 7 Down Inventory (7U7D)'''</big> * The 7 Up 7 Down Inventory is a recently developed and validated questionnaire with 14 items of manic and depressive tendencies carved from the General Behavior Inventory, a well-validated but cumbersome interview. For both mania and depression factors, 7 items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult)<ref name=":2">{{Cite journal|last=Youngstrom|first=Eric A.|last2=Murray|first2=Greg|last3=Johnson|first3=Sheri L.|last4=Findling|first4=Robert L.|date=2013-12|title=The 7 Up 7 Down Inventory: A 14-item measure of manic and depressive tendencies carved from the General Behavior Inventory|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970320/|journal=Psychological assessment|volume=25|issue=4|pages=1377–1383|doi=10.1037/a0033975|issn=1040-3590|pmc=PMC3970320|pmid=23914960}}</ref>.[https://en.wikiversity.org/wiki/OToPS/Measures/7_Up_7_Down_Inventory The 7 Up 7 Down Inventory, along with the accompanying research article can be found here] <big>'''Bipolar Spectrum Diagnostic Scale (BSDS)'''</big> *The Bipolar Spectrum Diagnostic Scale (BSDS) is a diagnostic tools that can assess for bipolar disorder in those who have Bipolar Disorder I, Bipolar Disorder II and Bipolar Disorder NOS. It was designed to help detect milder versions of bipolar disorder<ref name=":1">Zimmerman, M., Galione, J. N., Chelminski, I., Young, D. and Ruggero, C. J. (2010), Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. Bipolar Disorders, 12: 528–538. doi:10.1111/j.1399-5618.2010.00840.x</ref>. It is a self-report measure, and it has been shown to be generally effective in detecting bipolar disorder, though this effectiveness is not shown in individuals who have low insight.<ref name=":0">{{Cite journal|last=Nassir Ghaemi|first=S.|last2=Miller|first2=Christopher J.|last3=Berv|first3=Douglas A.|last4=Klugman|first4=Jeffry|last5=Rosenquist|first5=Klara J.|last6=Pies|first6=Ronald W.|date=February 2005|title=Sensitivity and specificity of a new bipolar spectrum diagnostic scale|url=https://www.ncbi.nlm.nih.gov/pubmed/15708426|journal=Journal of Affective Disorders|volume=84|issue=2-3|pages=273–277|doi=10.1016/S0165-0327(03)00196-4|issn=0165-0327|pmid=15708426}}</ref> The sensitivity of the BSDS is due to its focus on energy and drive rather than the mood symptoms present during hypomanic symptoms<ref name=":0" />. The threshold for a positive diagnosis is 13 points. The BSDS effectively screened out unipolar patients, maintained good sensitivity across the bipolar spectrum and low rate of false positives.<ref name=":0" />. <big>'''Mood Disorder Questionnaire (MDQ)'''</big> *The Mood Disorder Questionnaire (MDQ) is a self-report scale for bipolar disorder which focuses more on mood symptoms.<ref>Hirschfield, R., Williams, J., Spitzer R., Calabrese, J., Flynn L., Keck, P., Lewis L., McElroy S., Post, R., Rapport, D., Russel, J., Sachs, G., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. Am. J. Psychiatry 157, 1873-1875.</ref> It is very effective in detecting bipolar I disorder but less sensitive at detecting bipolar II disorder and Not Otherwise Specified (NOS).<ref>Miller, C., Ghaemi, S.N., Klugman, J., Berv, D.A., Pies, R.W., 2002. Utility of mood disorder questionnaire and bipolar spectrum diagnostic scale (Abstract). American Psychological Association Annual Meeting, Philadelphia, PA.</ref> {{collapse bottom}} === Interpreting adult bipolar disorder screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] * Also see the page on [[wikipedia:Likelihood_ratios_in_diagnostic_testing|likelihood ratios in diagnostic testing]] for more information ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID) | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS) | Semistructured interview | | | |- | General Behavior Inventory |Self-report | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} h54u3fvmq9m7c82fj3pqnexhe2et60u 2408195 2408193 2022-07-20T17:13:33Z Maddiegray11 2936309 /* Recommended diagnostic interviews for adult bipolar disorder */ Removed a screening measure from diagnostic tool table wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' !Clinical Generalizability |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical | |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical | |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical | |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. === More on high preforming bipolar screening measures === {{collapse top| Expand for more information}} <big>'''7 Up 7 Down Inventory (7U7D)'''</big> * The 7 Up 7 Down Inventory is a recently developed and validated questionnaire with 14 items of manic and depressive tendencies carved from the General Behavior Inventory, a well-validated but cumbersome interview. For both mania and depression factors, 7 items produced a psychometrically adequate measure applicable across both aggregate samples. Internal reliability of the Mania scale was .81 (youth) and .83 (adult) and for Depression was .93 (youth) and .95 (adult)<ref name=":2">{{Cite journal|last=Youngstrom|first=Eric A.|last2=Murray|first2=Greg|last3=Johnson|first3=Sheri L.|last4=Findling|first4=Robert L.|date=2013-12|title=The 7 Up 7 Down Inventory: A 14-item measure of manic and depressive tendencies carved from the General Behavior Inventory|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970320/|journal=Psychological assessment|volume=25|issue=4|pages=1377–1383|doi=10.1037/a0033975|issn=1040-3590|pmc=PMC3970320|pmid=23914960}}</ref>.[https://en.wikiversity.org/wiki/OToPS/Measures/7_Up_7_Down_Inventory The 7 Up 7 Down Inventory, along with the accompanying research article can be found here] <big>'''Bipolar Spectrum Diagnostic Scale (BSDS)'''</big> *The Bipolar Spectrum Diagnostic Scale (BSDS) is a diagnostic tools that can assess for bipolar disorder in those who have Bipolar Disorder I, Bipolar Disorder II and Bipolar Disorder NOS. It was designed to help detect milder versions of bipolar disorder<ref name=":1">Zimmerman, M., Galione, J. N., Chelminski, I., Young, D. and Ruggero, C. J. (2010), Performance of the Bipolar Spectrum Diagnostic Scale in psychiatric outpatients. Bipolar Disorders, 12: 528–538. doi:10.1111/j.1399-5618.2010.00840.x</ref>. It is a self-report measure, and it has been shown to be generally effective in detecting bipolar disorder, though this effectiveness is not shown in individuals who have low insight.<ref name=":0">{{Cite journal|last=Nassir Ghaemi|first=S.|last2=Miller|first2=Christopher J.|last3=Berv|first3=Douglas A.|last4=Klugman|first4=Jeffry|last5=Rosenquist|first5=Klara J.|last6=Pies|first6=Ronald W.|date=February 2005|title=Sensitivity and specificity of a new bipolar spectrum diagnostic scale|url=https://www.ncbi.nlm.nih.gov/pubmed/15708426|journal=Journal of Affective Disorders|volume=84|issue=2-3|pages=273–277|doi=10.1016/S0165-0327(03)00196-4|issn=0165-0327|pmid=15708426}}</ref> The sensitivity of the BSDS is due to its focus on energy and drive rather than the mood symptoms present during hypomanic symptoms<ref name=":0" />. The threshold for a positive diagnosis is 13 points. The BSDS effectively screened out unipolar patients, maintained good sensitivity across the bipolar spectrum and low rate of false positives.<ref name=":0" />. <big>'''Mood Disorder Questionnaire (MDQ)'''</big> *The Mood Disorder Questionnaire (MDQ) is a self-report scale for bipolar disorder which focuses more on mood symptoms.<ref>Hirschfield, R., Williams, J., Spitzer R., Calabrese, J., Flynn L., Keck, P., Lewis L., McElroy S., Post, R., Rapport, D., Russel, J., Sachs, G., Zajecka, J., 2000. Development and validation of a screening instrument for bipolar spectrum disorder: the mood disorder questionnaire. Am. J. Psychiatry 157, 1873-1875.</ref> It is very effective in detecting bipolar I disorder but less sensitive at detecting bipolar II disorder and Not Otherwise Specified (NOS).<ref>Miller, C., Ghaemi, S.N., Klugman, J., Berv, D.A., Pies, R.W., 2002. Utility of mood disorder questionnaire and bipolar spectrum diagnostic scale (Abstract). American Psychological Association Annual Meeting, Philadelphia, PA.</ref> {{collapse bottom}} === Interpreting adult bipolar disorder screening measure scores === * For information on interpreting screening measure scores, click [[Evidence based assessment/Prediction phase#Interpreting screening measure scores|here.]] * Also see the page on [[wikipedia:Likelihood_ratios_in_diagnostic_testing|likelihood ratios in diagnostic testing]] for more information ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID) | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS) | Semistructured interview | | | |- | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} 0u4ocszwuf8kts1yw3l79lbf0ns2nhq 2408196 2408195 2022-07-20T17:18:31Z Maddiegray11 2936309 /* Likelihood ratios and AUCs of screening measures for bipolar disorder in adults */ Took out extra wording and columns wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID) | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS) | Semistructured interview | | | |- | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} htbh3hib5dxgph2peg73azpp1d3mv4b 2408197 2408196 2022-07-20T17:19:42Z Maddiegray11 2936309 /* Recommended diagnostic interviews for adult bipolar disorder */ Added citations wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Process measures === There are many processes that may be considered important when evaluating an adult with Bipolar Disorder; however, due to the diversity of the population and symptom expression, there are too many to narrow down. Clinical judgment is recommended when deciding what additional measures should be included (e.g. executive functioning, sensory processing, cognitive flexibility). The measure provided below are commonly used to assess and provide important information regarding levels of daily functioning of individuals with Bipolar Disorder. {{blockquotetop}} More information on process measure coming soon. {{blockquotebottom}} === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} 4yex6d22ipipjfdl7t1j867kqdgobkq 2408241 2408197 2022-07-21T01:06:47Z Maddiegray11 2936309 /* Process measures */ Removed extra writing wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ===Severity interviews for bipolar disorder === {| class="wikitable sortable" border="1" |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time ! Interrater Reliability ! Test-Retest Reliability ! Construct Validity ! Content Validity ! Highly Recommended !Free and Accessible Measures |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |- | | | | | | | | | | |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} jbsw2aza049akzz1ef6hl1o5e90s62p 2408242 2408241 2022-07-21T01:20:53Z Maddiegray11 2936309 /* Severity interviews for bipolar disorder */ Added outcome measures without scores wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | Schedule for Affective Disorders and Schizophrenia (SADS)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | | | |- | | | | | |} ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | '''Mania Rating Scale (MAS)''' | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |- |'''The Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C)''' | | | | | | | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} ap1jhtgbqyx8fkwamnw0ppefmxcu1op 2408245 2408242 2022-07-21T01:34:36Z Maddiegray11 2936309 /* Recommended diagnostic interviews for adult bipolar disorder */ Added ages and time wikitext text/x-wiki <noinclude>{{Helping Give Away Psychological Science Banner}}</noinclude> {{medical disclaimer}} {{psychology}} {{Template:evidence-based assessment}} {{:{{BASEPAGENAME}}/Sidebar}} ==[[Evidence based assessment/Portfolio template/What is a "portfolio"|'''What is a "portfolio"?''']]== * For background information on what assessment portfolios are, click the link in the heading above. * Want even 'more' information about this topic? There's an extended version of this page [[Evidence-based assessment/Bipolar disorder in adults (assessment portfolio)/extended version|here]]. == [[Evidence based assessment/Preparation phase|'''Preparation phase''']] == === Diagnostic criteria for bipolar disorder in adults === Bipolar Disorder (BP) is characterized by extreme fluctuations in mood (or emotional dysregulation that ranges from mania (as shown by displays or feelings of extreme happiness, unrealistic overachievement and anger), to depression (as shown by displays or feelings of sadness, changes in appetite or weight and irritability.<ref name=":1" /> It has a lifetime risk of about 1%, with heritability estimated at up to 80%.<ref>{{Cite journal|last=Purcell|first=Shaun M.|last2=Wray|first2=Naomi R.|last3=Stone|first3=Jennifer L.|last4=Visscher|first4=Peter M.|last5=O'Donovan|first5=Michael C.|last6=Sullivan|first6=Patrick F.|last7=Sklar|first7=Pamela|last8=(Leader)|first8=Shaun M. Purcell|last9=Stone|first9=Jennifer L.|date=2009/08|title=Common polygenic variation contributes to risk of schizophrenia and bipolar disorder|url=http://www.nature.com/doifinder/10.1038/nature08185|journal=Nature|language=En|volume=460|issue=7256|doi=10.1038/nature08185|issn=1476-4687}}</ref> It is important to note that these moods exceed normal responses to life events, represent a change from the individual's normal functioning, and cause problems in daily activities. {{blockquotetop}} <big>'''ICD-11 Diagnostic Criteria'''</big> *Bipolar Type I Disorder **Bipolar type I disorder is an episodic mood disorder defined by the occurrence of one or more manic or mixed episodes. A manic episode is an extreme mood state lasting at least one week unless shortened by a treatment intervention characterized by euphoria, irritability, or expansiveness, and by increased activity or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid or pressured speech, flight of ideas, increased self-esteem or grandiosity, decreased need for sleep, distractibility, impulsive or reckless behavior, and rapid changes among different mood states (i.e., mood lability). A mixed episode is characterized by either a mixture or very rapid alternation between prominent manic and depressive symptoms on most days during a period of at least 2 weeks. Although the diagnosis can be made based on evidence of a single manic or mixed episode, typically manic or mixed episodes alternate with depressive episodes over the course of the disorder. ***Note: The ICD-11 lists 18 additional subcategories of Bipolar type I disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/1456478153 here]. *Bipolar Type II Disorder **Bipolar type II disorder is an episodic mood disorder defined by the occurrence of one or more hypomanic episodes and at least one depressive episode. A hypomanic episode is a persistent mood state characterized by euphoria, irritability, or expansiveness, and excessive psychomotor activation or increased energy, accompanied by other characteristic symptoms such as grandiosity, decreased need for sleep, pressured speech, flight of ideas, distractibility, and impulsive or reckless behavior lasting for at least several days. The symptoms represent a change from the individual’s typical behavior and are not severe enough to cause marked impairment in functioning. A depressive episode is characterized by a period of almost daily depressed mood or diminished interest in activities lasting at least 2 weeks accompanied by other symptoms such as changes in appetite or sleep, psychomotor agitation or retardation, fatigue, feelings of worthless or excessive or inappropriate guilt, feelings or hopelessness, difficulty concentrating, and suicidality. There is no history of manic or mixed Episodes. ***Note: The ICD-11 lists 13 additional subcategories of Bipolar type II disorder. They can be found [https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f199053300 here]. '''Changes in DSM-5''' * The diagnostic criteria for '''Bipolar Disorder''' changed slightly from [[DSM-IV]] to [[w:Diagnostic_and_Statistical_Manual_of_Mental_Disorders#DSM-IV-TR_.282000.29|DSM-5]]. Summaries are available [http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf here] and [[w:DSM-5|here]]. {{blockquotebottom}} === Base rates of BD in different clinical settings and populations === This section describes the demographic setting of the population(s) sampled, base rates of diagnosis, country/region sampled, and the diagnostic method that was used. Using this information, clinicians will be able to anchor the rate of adolescent depression that they are likely to see in their clinical practice. * '''''To see prevalence rates across multiple disorders,''''' [[Evidence based assessment/Preparation phase#Base rates for transdiagnostic comparison|'''''click here.''''']] {| class="wikitable" |'''Demography''' |'''Setting''' |'''Base Rate''' |'''Diagnostic Method''' |- |United States, Canada, Puerto Rico, Germany, Taiwan, Korea, New Zealand <ref>{{Cite journal|last=Weissman|first=Myrna M.|last2=Bland|first2=Roger C.|last3=Canino|first3=Glorisa J.|last4=Faravelli|first4=Carlo|last5=Greenwald|first5=Steven|last6=Hwu|first6=Hai-Gwo|last7=Joyce|first7=Peter R.|last8=Karam|first8=Eile G.|last9=Lee|first9=Chung-Kyoon|date=1996-07-24|title=Cross-National Epidemiology of Major Depression and Bipolar Disorder|url=https://doi.org/10.1001/jama.1996.03540040037030|journal=JAMA|volume=276|issue=4|pages=293–299|doi=10.1001/jama.1996.03540040037030|issn=0098-7484}}</ref> |Community Epidemiological Samples |0.3 - 1.5% |Structured and semi-structured diagnostic interviews |- |United States<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Akiskal|first2=Hagop S.|last3=Angst|first3=Jules|last4=Greenberg|first4=Paul E.|last5=Hirschfeld|first5=Robert M. A.|last6=Petukhova|first6=Maria|last7=Kessler|first7=Ronald C.|date=2007-05-01|title=Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication|url=https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482285|journal=Archives of General Psychiatry|language=en|volume=64|issue=5|pages=543–552|doi=10.1001/archpsyc.64.5.543|issn=0003-990X}}</ref> |Community Epidemiological Samples |BPI - 1%; BPII - 1.1%; Subthreshold BP - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=LEWINSOHN|first=PETER M.|last2=KLEIN|first2=DANIEL N.|last3=SEELEY|first3=JOHN R.|title=Bipolar Disorders in a Community Sample of Older Adolescents: Prevalence, Phenomenology, Comorbidity, and Course|url=http://linkinghub.elsevier.com/retrieve/pii/S089085670963731X|journal=Journal of the American Academy of Child & Adolescent Psychiatry|volume=34|issue=4|pages=454–463|doi=10.1097/00004583-199504000-00012}}</ref> |Community samples (older adolescents) |1% |K-SADS Semi-Structured Interview |- |United States<ref>{{Cite journal|last=Judd|first=Lewis L.|last2=Akiskal|first2=Hagop S.|title=The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases|url=https://doi.org/10.1016/S0165-0327(02)00332-4|journal=Journal of Affective Disorders|volume=73|issue=1-2|pages=123–131|doi=10.1016/s0165-0327(02)00332-4}}</ref> |US National Epidemiological Catchment Area (ECA) database |0.8 - 5.1% (manic and subthreshold mania) |Diagnostic Interview Schedule (DIS) |- |United States<ref>{{Cite journal|last=Kessler|first=R. C.|last2=Rubinow|first2=D. R.|last3=Holmes|first3=C.|last4=Abelson|first4=J. M.|last5=Zhao|first5=S.|date=1997/09|title=The epidemiology of DSM-III-R bipolar I disorder in a general population survey|url=https://www.cambridge.org/core/journals/psychological-medicine/article/epidemiology-of-dsmiiir-bipolar-i-disorder-in-a-general-population-survey/950D518D15F64E2059F1033558615A9A|journal=Psychological Medicine|language=en|volume=27|issue=5|pages=1079–1089|issn=1469-8978}}</ref> |US National Comorbidity Survey (NCS) |0-4% (small community sample; reappraisal study) |World Health Organisation Composite International Diagnostic Interview |- |United States and other countries<ref>{{Cite book|url=https://www.worldcat.org/oclc/830807378|title=Diagnostic and statistical manual of mental disorders : DSM-5.|date=2013|publisher=American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force.|isbn=9780890425541|edition=5th|location=Arlington, VA|oclc=830807378}}</ref> |Community sample |BPI - 0.6%; BPII-  1.8%;  Cyclothymia - 0.4-1% |Unspecified |- |United States, Europe, Asia<ref>{{Cite journal|last=Merikangas|first=Kathleen R.|last2=Jin|first2=Robert|last3=He|first3=Jian-Ping|last4=Kessler|first4=Ronald C.|last5=Lee|first5=Sing|last6=Sampson|first6=Nancy A.|last7=Viana|first7=Maria Carmen|last8=Andrade|first8=Laura Helena|last9=Hu|first9=Chiyi|date=2011-03-07|title=Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archgenpsychiatry.2011.12|journal=Archives of General Psychiatry|language=en|volume=68|issue=3|doi=10.1001/archgenpsychiatry.2011.12|issn=0003-990X}}</ref> |Community Samples |BPI - 0.6%; BPII - 0.4%; Subthreshold BP - 1.4%; Bipolar Spectrum Disorder - 2.4% |World Health Organisation Composite International Diagnostic Interview |- |United States<ref>{{Cite journal|last=Grant|first=Bridget F.|last2=Stinson|first2=Frederick S.|last3=Hasin|first3=Deborah S.|last4=Dawson|first4=Deborah A.|last5=Chou|first5=S. Patricia|last6=Ruan|first6=W. June|last7=Huang|first7=Boji|date=October 2005|title=Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions|url=https://www.ncbi.nlm.nih.gov/pubmed/16259532|journal=The Journal of Clinical Psychiatry|volume=66|issue=10|pages=1205–1215|issn=0160-6689|pmid=16259532}}</ref> |National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) |BPI - 3.3% |The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV) |- |United States<ref>{{Cite journal|last=Das|first=Amar K.|date=2005-02-23|title=Screening for Bipolar Disorder in a Primary Care Practice|url=http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.293.8.956|journal=JAMA|language=en|volume=293|issue=8|doi=10.1001/jama.293.8.956|issn=0098-7484}}</ref> |Outpatient Clinic Sample |9.8% |Review of medical records, questionnaire data |- |United States<ref>{{cite journal|last1=Hirschfeld|first1=RM|last2=Cass|first2=AR|last3=Holt|first3=DC|last4=Carlson|first4=CA|date=2005|title=Screening for bipolar disorder in patients treated for depression in a family medicine clinic.|journal=The Journal of the American Board of Family Practice|volume=18|issue=4|pages=233-9|pmid=15994469}}</ref> |Outpatient Clinic Sample |21.3% |MDQ, SCID |} ==[[Evidence based assessment/Prediction phase|'''Prediction phase''']]== === Psychometric properties of screening instruments for adult bipolar disorder === The following section contains a list of screening and diagnostic instruments for adult bipolar disorder. The section includes administration information, psychometric data, and PDFs or links to the screenings. * Screenings are used as part of the [[Evidence based assessment/Prediction phase|prediction phase]] of assessment; for more information on interpretation of this data, or how screenings fit in to the assessment process, click [[Evidence based assessment/Prediction phase|here.]] * '''''For a list of more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Psychometric_properties_of_common_screening_instruments click here.]''''' {| class="wikitable" |- ! Measure !Format (Reporter) !Age Range !Administration/ Completion Time !Where to Access |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /><ref>{{Cite journal|last=Feng|first=Yuan|last2=Wang|first2=Yuan-Yuan|last3=Huang|first3=Wei|last4=Ungvari|first4=Gabor S.|last5=Ng|first5=Chee H.|last6=Wang|first6=Gang|last7=Yuan|first7=Zhen|last8=Xiang|first8=Yu-Tao|date=2017-06-01|title=Comparison of the 32-item Hypomania Checklist, the 33-item Hypomania Checklist, and the Mood Disorders Questionnaire for bipolar disorder|url=http://onlinelibrary.wiley.com/doi/10.1111/pcn.12506/abstract|journal=Psychiatry and Clinical Neurosciences|language=en|volume=71|issue=6|pages=403–408|doi=10.1111/pcn.12506|issn=1440-1819}}</ref> |Self-report |Adult |10-15 minutes | * [https://mfr.osf.io/render?url=https://osf.io/2veyc/?action=download%26mode=render Self-report] |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]]<ref name="Carvalho" /> |Self-report |Adult |15 minutes | * [http://psycheducation.org/diagnosis/the-bipolar-spectrum-diagnostic-scale/ Online version] * [https://mfr.osf.io/render?url=https://osf.io/w9qet/?action=download%26mode=render Downloadable PDF Version (English)] |- |[[wikipedia:General_Behavior_Inventory|GBI (General Behavior Inventory)]] |Self-report |Adult |15-20 minutes | * [https://mfr.osf.io/render?url=https://osf.io/j6rce/?action=download%26mode=render Downloadable PDF Self-Report English] * [https://mfr.osf.io/render?url=https://osf.io/27nwg/?action=download%26mode=render Scoring instructions and information] |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |Self-report |Adult |5 minutes | * [https://mfr.osf.io/render?url=https://osf.io/sb5xw/?action=download%26mode=render Adult Self-Report (Long, English)] * [https://mfr.osf.io/render?url=https://osf.io/xa7v6/?action=download%26mode=render Adult Self-Report (Short, English)] * |} '''Note:''' '''L''' = Less than adequate; '''A''' = Adequate; '''G''' = Good; '''E''' = Excellent; '''U''' = Unavailable; '''NA''' = Not applicable === Likelihood ratios and AUCs of screening measures for bipolar disorder in adults === * '''''For a list of the likelihood ratios for more broadly reaching screening instruments, [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prediction_phase&wteswitched=1#Likelihood_ratios_and_AUCs_of_common_screening_instruments click here.]''''' {| class="wikitable sortable" !'''Screening Measure (Primary Reference)''' !'''Area Under Curve (AUC) and sample size''' !'''DiLR+ (score)''' !DiLR- (score) !'''Population''' |- |[[wikipedia:Bipolar_Spectrum_Diagnostic_Scale|BSDS (Bipolar Spectrum Diagnostic Scale)]] <ref name="Carvalho" /> |0.81 |(13) <ref name = Carvalho>{{cite journal|last1=Carvalho|first1=André F.|last2=Takwoingi|first2=Yemisi|last3=Sales|first3=Paulo Marcelo G.|last4=Soczynska|first4=Joanna K.|last5=Köhler|first5=Cristiano A.|last6=Freitas|first6=Thiago H.|last7=Quevedo|first7=João|last8=Hyphantis|first8=Thomas N.|last9=McIntyre|first9=Roger S.|last10=Vieta|first10=Eduard|title=Screening for bipolar spectrum disorders: A comprehensive meta-analysis of accuracy studies|journal=Journal of Affective Disorders|date=February 2015|volume=172|pages=337–346|doi=https://doi.org/10.1016/j.jad.2014.10.024}}</ref> |0.36 (4.93) |Clinical |- |[[wikipedia:Hypomania_Checklist|HCL-32 (Hypomania Checklist)]]<ref name="Carvalho" /> |0.80 |(14)<ref name="Carvalho" /> |0.28 (2.45) |Clinical |- |[[wikipedia:Mood_Disorder_Questionnaire|MDQ (Mood Disorder Questionnaire)]]<ref name="Carvalho" /> |0.78 |(7)<ref name="Carvalho" /> |0.22 (5.4) |Clinical |} '''Note:''' Area Under Curve (AUC, or AUROC) is equal to the probability that a classifier will rank a randomly chosen positive diagnosis of Bipolar Disorder higher than a randomly chosen negative diagnosis of Bipolar Disorder[15]. ==[[Evidence based assessment/Prescription phase|'''Prescription phase''']]== ===Gold standard diagnostic interviews=== * For a list of broad reaching diagnostic interviews sortable by disorder with PDFs (if applicable), [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Prescription_phase&wteswitched=1#Common_Diagnostic_Interviews click here.] ===Recommended diagnostic interviews for adult bipolar disorder=== {| class="wikitable sortable" border="1" ! colspan="5" |Diagnostic instruments for BPSD |- ! Measure ! Format (Reporter) ! Age Range ! Administration/ Completion Time !Where to Access |- | Structured Clinical Interview for DSM-5 (SCID)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref> | Semistructured interview | 18+ | 1-2 hours |Available for purchase from [https://www.appi.org/products/structured-clinical-interview-for-dsm-5-scid-5 APA Publishing] |- | Schedule for Affective Disorders and Schizophrenia (SADS)<ref>{{Cite journal|last=Miller|first=Christopher J.|last2=Johnson|first2=Sheri L.|last3=Eisner|first3=Lori|date=2009-06|title=Assessment tools for adult bipolar disorder.|url=http://doi.apa.org/getdoi.cfm?doi=10.1111/j.1468-2850.2009.01158.x|journal=Clinical Psychology: Science and Practice|language=en|volume=16|issue=2|pages=188–201|doi=10.1111/j.1468-2850.2009.01158.x|issn=1468-2850|pmc=PMC2847794|pmid=20360999}}</ref><ref>{{Cite journal|last=Endicott|first=Jean|date=1978-07-01|title=A Diagnostic Interview: The Schedule for Affective Disorders and Schizophrenia|url=http://archpsyc.jamanetwork.com/article.aspx?doi=10.1001/archpsyc.1978.01770310043002|journal=Archives of General Psychiatry|language=en|volume=35|issue=7|pages=837|doi=10.1001/archpsyc.1978.01770310043002|issn=0003-990X}}</ref> | Semistructured interview | 18+ | 1-2 hours | |- | | | | | |} ==[[Evidence based assessment/Process phase|'''Process phase''']]== The following section contains a list of process and outcome measures for bipolar disorder in adults. The section includes benchmarks based on published norms and on mood samples for several outcome and severity measures, as well as information about commonly used process measures. Process and outcome measures are used as part of the [[Evidence based assessment/Process phase|process phase]] of assessment. For more information of differences between process and outcome measures, see the page on the [[Evidence based assessment/Process phase|process phase of assessment]]. === Outcome and severity measures === This table includes clinically significant benchmarks for adult bipolar disorder specific outcome measures * Information on how to interpret this table can be [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase '''found here''']. * Additionally, these [[Evidence based assessment/Vignettes|vignettes]] might be helpful resources for understanding appropriate adaptation of outcome measures in practice. *''<u>For clinically significant change benchmarks for the CBCL, YSR, and TRF total, externalizing, internalizing, and attention benchmarks,</u>'' [https://en.wikiversity.org/w/index.php?title=Evidence_based_assessment/Process_phase&wteswitched=1#Clinically_significant_change_benchmarks_for_widely-used_outcome_measures '''see here.'''] {| class="wikitable sortable" border="1" | colspan="8" |'''Clinically significant change benchmarks with common instruments for bipolar disorder''' |- | colspan="8" span style="font-size:110%; text-align:center;" | <b> Benchmarks Based on Published Norms </b> |- | rowspan="2" style="text-align:center;font-size:130%;" |<b> Measure</b> | rowspan="2" style="text-align:center;font-size:130%;" | <b>Subscale</b> | colspan="3" style="text-align:center;font-size:130%" width="300" | <b> Cut-off scores</b> | colspan="3" style="text-align:center;font-size:120%" | <b> Critical Change <br> (unstandardized scores)</b> |- | style="text-align:center;font-size:110%" | <b> A</b> | style="text-align:center;font-size:110%" |<b> B</b> | style="text-align:center;font-size:110%" |<b> C</b> | style="text-align:center;font-size:110%" |<b> 95%</b> | style="text-align:center;font-size:110%" |<b> 90%</b> | style="text-align:center;font-size:110%" |<b> SE_difference</b> |- | rowspan="1" style="text-align:center;" |<b> CBCL T-scores <br> (2001 Norms)</b> | style="text-align:right;" |<i> Total</i> | style="text-align:center;" | 49 | style="text-align:center;" | 70 | style="text-align:center;" | 58 | style="text-align:center;" | 5 | style="text-align:center;" | 4 | style="text-align:center;" | 2.4 |- | rowspan="1" style="text-align:center;" | '''Mania Rating Scale (MAS)''' | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | | style="text-align:center;" | |- |'''The Schedule for Affective Disorders and Schizophrenia-Change Version (SADS-C)''' | | | | | | | |} === Treatment === * Please refer to the page on [https://en.wikipedia.org/wiki/Bipolar_disorder bipolar disorder] for more information on available treatment for bipolar disorder or go to the Effective Child Therapy pages for [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/| Severe Mood Swings & Bipolar Spectrum Disorders] * [https://reacttoolkit.uk/ Relatives Education and Coping Toolkit (REACT)] is currently freely available at https://reacttoolkit.uk/. This is a resource/project of [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ The Sprectrum Centre for Mental Health Research] from Lancaster University. A team of clinicians, researchers and relatives of people with psychosis or bipolar disorder at Lancaster, Liverpool and London have developed the Relatives Education and Coping Toolkit (REACT). REACT provides [https://www.nice.org.uk/ National Institute for Health and Care Excellence (NICE)] recommended information and support to relatives and friends of people with mental health problems associated with psychosis or bipolar disorder through a digital, peer-supported, self-management toolkit.<ref>Lobban, A. F., Robinson, H. A., Appelbe, D., Barraclough, J., Bedson, E., Collinge, E., Dodd, S., Flowers, S., Honary, M., Johnson, S., Caixeiro Mateus, M. D. C., Mezes, B., Minns, V., Murray, E., Walker, A. J., Williamson, P., Wintermeyer, C., & Jones, S. H. (2017). Protocol for an online randomised controlled trial to evaluate the clinical and cost-effectiveness of a peer-supported self-management intervention for relatives of people with psychosis or bipolar disorder: Relatives Education And Coping Toolkit (REACT). BMJ Open, 7, [016965]. <nowiki>https://doi.org/10.1136/bmjopen-2017-016965</nowiki></ref><ref>Lobban, F., Akers, N., Appelbe, D., Chapman, L., Collinge, L., Dodd, S., Flowers, S., Hollingsworth, B., Johnson, S., Jones, S. H., Mateus, C., Mezes, B., Murray, E., Panagaki, K., Rainford, N., Robinson, H., Rosala-Hallas, A., Sellwood, W., Walker, A., & Williamson, P. (2020). Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial. BMC Psychiatry, 20(1), [160]. <nowiki>https://doi.org/10.1186/s12888-020-02545-9</nowiki></ref><ref>{{Cite journal|last=F|first=Lobban|last2=N|first2=Akers|last3=D|first3=Appelbe|last4=R|first4=Iraci Capuccinello|last5=L|first5=Chapman|last6=L|first6=Collinge|last7=S|first7=Dodd|last8=S|first8=Flowers|last9=B|first9=Hollingsworth|date=2020-07-01|title=A web-based, peer-supported self-management intervention to reduce distress in relatives of people with psychosis or bipolar disorder: the REACT RCT|url=https://www.journalslibrary.nihr.ac.uk/hta/hta24320|journal=Health Technology Assessment|language=EN|volume=24|issue=32|doi=10.3310/hta24320|issn=2046-4924|pmc=PMC7355407|pmid=32608353}}</ref> ** The team at Spectrum Centre also conducted a study linked to REACT called IMPART which looked at what would happen if they tried to deliver REACT as part of routine clinical care in Early Intervention Teams in the [https://www.nhs.uk/ United Kingdom's National Health Service (NHS)]. This study identified key factors that impact implementation and may be useful for informing implementation plans for other digital health interventions.<ref>{{Cite journal|last=Lobban|first=Fiona|last2=Appelbe|first2=Duncan|last3=Appleton|first3=Victoria|last4=Billsborough|first4=Julie|last5=Fisher|first5=Naomi Ruth|last6=Foster|first6=Sheena|last7=Gill|first7=Bethany|last8=Glentworth|first8=David|last9=Harrop|first9=Chris|date=2020-03-17|title=IMPlementation of An online Relatives’ Toolkit for psychosis or bipolar (IMPART study): iterative multiple case study to identify key factors impacting on staff uptake and use|url=https://doi.org/10.1186/s12913-020-5002-4|journal=BMC Health Services Research|volume=20|issue=1|pages=219|doi=10.1186/s12913-020-5002-4|issn=1472-6963|pmc=PMC7077000|pmid=32183787}}</ref> ** '''[https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ RECOVERY TOOLKIT]''' #eRecoveryToolkit, #RecoveryBD, #PersonalRecovery is freely accessible at https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/. Inspired from a greater body of work around recovery, people with lived experience of bipolar disorder and researchers at [https://www.lancaster.ac.uk/health-and-medicine/research/spectrum/ Spectrum Centre] have created a multi-media recovery toolkit. The aim of the toolkit is to provide accessible information and promote discussion around personal discovery in order to understand and aid people’s recovery journeys. The toolkit contains an animation, an e-booklet and video narratives of relatives and clinicians.<ref>Beck, A. K., Baker, A., Jones, S. H., Lobban, A. F., Kay-Lambkin, F., Attia, J., & Banfield, M. (2018). Exploring the feasibility and acceptability of a recovery-focused group therapy intervention for adults with bipolar disorder: trial protocol. BMJ Open, 8, [e019203]. <nowiki>https://doi.org/10.1136/bmjopen-2017-019203</nowiki></ref> {| cellspacing="0" style="width:238px;" | style="width:45px; height:45px; background:#d1f3f5; color:#49dae9; text-align:center;" vertical-align="center" align="center"| '''<span style="font-size:24pt;">t</span>''' | style="background:#b7eef0; color:black; font-size:8pt; padding:4pt; line-height:1.25em;"| This user tweets on '''[[w:Twitter|Twitter]]''' as [http://twitter.com/_REACTTOOLKIT REACTTOOLKIT]. |} == '''External resources''' == # [http://apps.who.int/classifications/icd10/browse/2015/en#/F31 ICD-10 diagnostic criteria] # [https://en.wikiversity.org/w/index.php?title=Helping_Give_Away_Psychological_Science/Resources/Annotated_List_of_Where_and_How_to_Find_a_Therapist&wteswitched=1#Other_low-cost_options Find-a-Therapist] (a curated list of find-a-therapist websites where you can find a provider) # OMIM (Online Mendelian Inheritance in Man) ## [http://omim.org/entry/125480 125480] ## [http://omim.org/entry/611536 611536] ## [http://omim.org/entry/309200 309200,] ## [http://omim.org/entry/611535 611535] ## [http://omim.org/entry/603663 603663] # [https://emedicine.medscape.com/article/286342-overview eMedicine information] # [http://effectivechildtherapy.org/concerns-symptoms-disorders/disorders/severe-mood-swings-and-bipolar-spectrum-disorders/ Effective Child Therapy information on Bipolar Disorder] #*Effective Child Therapy is website sponsored by Division 53 of the American Psychological Association (APA), or [https://sccap53.org The Society of Clinical Child and Adolescent Psychology](SCCAP), in collaboration with the Association for Behavioral and Cognitive Therapies (ABCT). Use for information on symptoms and available treatments. # The Psych Show with Dr. Ali Mattu videos (geared towards public; might send to client) ##[https://www.youtube.com/watch?v=llOPqKD-s4w How to Cope with Bipolar Disorder] ## [https://www.youtube.com/watch?v=kUHUmeqBZAA Top 10 Bipolar Myths] == '''References''' == {{collapse top|Click here for references}} {{Reflist|30em}} [[Category:Psychological disorder portfolios|{{SUBPAGENAME}}]] {{collapse bottom}} hyqp259y61rjqv5v7eom2e8vafgu3f3 0 242365 2408313 2347968 2022-07-21T05:56:21Z Congariel 2946865 Improving the article as may be the initiator do not know how to speak Syloti. But thanks.. wikitext text/x-wiki {{Center|{{huge|'''ꠍꠤꠟꠐꠤ'''}}<br>{{big|'''''Silôṭi maṭ'''''}}<br>{{big|''Syloti language''}}}} {{languages}} {{lesson}} {{51%done-2}} This course is intended to teach the '''{{w|Syloti language}}'''. == Who is this course for? == This is a comprehensive course for people who want to develop linguistic (lexical, grammatical and phonetic) and communication skills in the Sylheti language. ==First contact== Let's dive straight into some simple Sylheti sentences to give you a first impression of how Sylheti is structured. Sentence 1 : I speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি<br> si•lo•ṭi !! মাতি <br> ma•ti |- | I || Syloti || speak. |- | Subject || Direct Object || Verb |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> le = লে <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> b = ব<br> ba = বা<br> bang = বাং <br> lo = ল <br> la = লা<br> = <br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি |} Note : The simple affirmative present tense Syloti sentence follows the Subject-Object-Verb (SOV) word order. Sentence 2 : I do not speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি <br> si•lo•ṭi !! মাতি <br> ma•ti !! না <br> naa. |- | I || Syloti || speak || not |- | Subject || Direct Object || Verb || Negative marker for present |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> lo = ল <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি || n = ন <br> na = না |} Note : The simple negative present tense Sylheti sentence adds the negative marker -naa after the verb to make it negative. Note : 1. As the subject changes from ami (I) to tumi (You), observe that the form of the present tense verb changes. To learn more about this, see [[/Verbs/]] == List of Grammar Lessons (not in order) == * Lesson x. [[/Pronouns/]] * Lesson x. [[/Nouns/]] * Lesson x. [[/Verbs/]] * Lesson x. [[/Adjectives/]] * Lesson x. [[/Adverbs/]] * Lesson x. [[/Degree Modifiers for adjectives, adverbs and verbs/]] * Lesson x. [[/Comparison with nouns, adjectives, adverbs and verbs/]] * Lesson x. [[/Object Pronouns/]] * Lesson x. [[/Word Order/]] * Lesson x. [[/Postpositions/]] * Lesson x. [[/Expressing temporal information/]] ('''When''' or '''how often''' something happens) * Lesson x. [[/Expressing locative information/]] ('''Where''' something happens) * Lesson x. [[/Expressing Obligation with Verb/]] (modal auxiliary "zoruri") * Lesson x. [[/Expressing Possibility with Verb/]] (modal auxiliary "fara") * Lesson x. [[/Expressing Ability or Knowhow with Verb/]] (modal auxiliary "zana" or "fara") * Lesson x. [[/Expressing Want with Verb/]] (modal auxiliary "saua") * Lesson x. [[/Expressing Need with Verb/]] (modal auxiliary "dorkhar" or "laga") * Lesson x. [[/Expressing Cause/]] ('''Why''' something happens) * Lesson x. [[/Expressing Consequence/]] * Lesson x. [[/Expressing Goal/]] ('''For what''' something happens) * Lesson x. [[/Expressing Opposition/]] (how to say ''but, on the contrary, however,'' etc.) * Lesson x. [[/Expressing Addition of Ideas/]] (how to say ''and, moreover,'' etc) * Lesson x. [[/Expressing Conditions/]] (how to say ''if, unless, depends'' etc) * Lesson x. [[/Expressing Anteriority, Posteriority and Simultaneity/]] (how to say ''before, after, during'' etc) * Lesson x. [[/Characterizing using relative clauses/]] (how to add information using ''who, which, where, whose, that'' etc) * Lesson x. [[/Asking Questions/]] ==List of Vocabulary Lessons (not in order)== * Lesson x. [[/Greetings and basic polite expressions/]] * Lesson x. [[/Numbers/]] * Lesson x. [[/Measurements and Quantities/]] * Lesson x. [[/Characteristics of Objects/]]: Size, Shape, Material, Texture, Color * Lesson x. [[/Geography and nationalities/]] * Lesson x. [[/Languages/]] * Lesson x. [[/Human Body/]] * Lesson x. [[/Movements, Gestures and Postures/]] * Lesson x. [[/Cycle of Life/]] * Lesson x. [[/Family/]] * Lesson x. [[/Relationships/]] * Lesson x. [[/Personal Information/]] * Lesson x. [[/Daily activities/]] * Lesson x. [[/Housing/]] * Lesson x. [[/Appearance and Clothing/]] * Lesson x. [[/Places in the city/]] * Lesson x. [[/Directions/]] * Lesson x. [[/Traveling, roads and transport/]] * Lesson x. [[/Personal Objects/]] * Lesson x. [[/Education/]] * Lesson x. [[/Work and Workplaces/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Vacation/]] * Lesson x. [[/Leisure activities/]] * Lesson x. [[/Animals/]] * Lesson x. [[/Plants and Trees/]] * Lesson x. [[/Food/]] * Lesson x. [[/Eating out/]] * Lesson x. [[/Cooking, Recipes and Gastronomy/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Graphic Arts/]] * Lesson x. [[/Theater/]] * Lesson x. [[/Cinema/]] * Lesson x. [[/Music/]] * Lesson x. [[/Architecture/]] * Lesson x. [[/Photography/]] * Lesson x. [[/Sports and games/]] * Lesson x. [[/Post office and other services/]] * Lesson x. [[/Media/]] * Lesson x. [[/Computers and Internet/]] * Lesson x. [[/Books and literature/]] * Lesson x. [[/Intellectual life/]] * Lesson x. [[/Communication/]] * Lesson x. [[/Feelings and Emotions/]] * Lesson x. [[/Health and Medicine/]] * Lesson x. [[/Fashion/]] * Lesson x. [[/Money and Banking/]] * Lesson x. [[/Character and Personality/]] * Lesson x. [[/Science and Research/]] * Lesson x. [[/Crime, Law and Justice/]] * Lesson x. [[/Environment/]] * Lesson x. [[/Weather and Climate/]] * Lesson x. [[/Economy and Finances/]] * Lesson x. [[/Politics/]] * Lesson x. [[/Social Issues/]] * Lesson x. [[/Morality/]] * Lesson x. [[/Mind and psychology/]] * Lesson x. [[/Time/]] * Lesson x. [[/The Past/]] * Lesson x. [[/The Future/]] * Lesson x. [[/Belief and religion/]] ==Appendices== * Appendix x. [[/Foreign words/]] [[Category:Sylheti Dialect]] ry7siw5lgo8rqdcc2jwggy6f61hme7w 2408315 2408313 2022-07-21T05:58:15Z Congariel 2946865 Redirected page to [[Syloti language]] wikitext text/x-wiki #REDIRECT [[Syloti language]] byj4fyxzvu3yierma0tg0jnsfpo0krn 0 261965 2408240 2405762 2022-07-21T00:45:01Z LinzCarey 2848224 UPdated references wikitext text/x-wiki == Speech-Language Pathology in Palliative Care – Special Interest Group == __TOC__ == Introduction == Speech-Language Pathology (SLP) in Palliative Care (PalCare) is a new and developing area of specialty which aims to provide appropriate SLP practice within palliative and end-of-life care services. While the profession of [[:w:Speech-language pathology|speech-language pathology/speech therapy]] has been in existence since the turn of the 20th Century, and [[:w:Palliative care|palliative care]] has been practiced for centuries (in one form or another), nevertheless, the combination of the two disciplinary areas intersecting has often been intermittent and highly dependent upon a specific institutional context, rather than being systematically endorsed by any government regulations or professional association clinical practice guidelines (CPGs). == SLP-PalCare Focus == Speech-Language Pathology in Palliative Care Special Interest Group has a primary focus upon ten major areas in order to support SLPs in Palliative Care and redress the lack of SLP CPGs in Palliative Care:[https://www.tandfonline.com/doi/full/10.1080/17549507.2020.1730966 Chahda et al (2020)] # Encouraging, developing and/or conducting ongoing research and creating resources for SLPs working in Palliative Care. # Educating health professions about the role of SLPs in PalCare. # Establishing referral procedures for SLP intervention within PalCare. # Integrating PalCare within SLP tertiary education. # Promoting the education, consultation, supervision and mentoring of SLPs new to PalCare. # Incorporating SLP observations and interventions into the overall multi-disciplinary/palliative care team goals. # Focussing PalCare assessment and therapy to include both cognitive-communication and swallowing interventions. # Integration of SLPs as a part of a practical, consultative and holistic PalCare approach. # Encouraging professional self-care consideration for SLPs working in PalCare. # The development of uniform SLP-PalCare CPGs == Research and Future Development == Based upon the findings of an increasing number of researchers [for example see the reviews of [https://doi.org/10.1080/17549507.2016.1241301 Chahda et al (2017)] and [https://doi.org/10.1080/17549507.2017.1337225 Krikheli et al (2018)] there is clearly a need for further research and increased scope of practice accompanied by the development of SLP clinical practice guidelines so as to enhance the multidisciplinary and holistic collaboration of SLPs within Palliative Care contexts. ==== CURRENT RESEARCH (2022) ==== '''"Identifing facilitators and barriers to successful speech pathology student placements in the palliative care setting"''' '''Time frame:'''  May to August 2022 '''Survey:''' Completed. '''Focus Groups''': Completed. '''Interviews:''' Planning This project is being completed by researchers from The University of Melbourne and Deakin University. * Dr Laura Chahda (Email: laura.chahda@unimelb.edu.au) * Dr Megan Keage (Email: megan.keage@unimelb.edu.au) * Ms Hayley Dell’Oro (Email: hayley.delloro@unimelb.edu) * Dr Jemma Skeat (Email: jemma.skeat@deakin.edu.au) '''"The PCC4U (Palliative Care Curriculum for Undergraduates"''': https://pcc4u.org.au/) assists in providing resources for the trainng of undergradutes in palliative care and provides a number of resources incuding vdieo case studies: (access via: https://www.youtube.com/user/PCC4UProject/playlists) one of which mentions SLPs: (https://pcc4u.org.au/learning/modules/module4/m4_section3/m4_activity8/). == SLP-PalCare-SIG Representatives & Membership == To achieve the objective foci of SLPs within Palliative Care (as noted above) the formation of the 'Speech-Language Pathology and Palliative Care Special Interest Group' (SLP-PalCare-SIG) has been listed by [https://www.speechpathologyaustralia.org.au/SPAweb/Resources_For_Speech_Pathologists/Non_SPA_Resources/Special_Interest_Groups/SPAweb/Resources_for_Speech_Pathologists/Non_SPA_Resources/Special_Interest_Groups.aspx?hkey=c1a0adee-4577-45e1-9c1e-31ee203f2789 '''Speech Pathology Australia'''] (SPA) and currently involves representatives from a number of universities and clinical practices. There is no fee to be a member of the SLP-PalCare-SIG. Please email the secretary if you are interested in joining. ''SLP-PalCare-SIG Members (Alphabetical by Surname):'' * [Chairperson] Professor. Bernice Mathisen (University of Southern Queensland, AU: Bernice.Mathisen@usq.edu.au) * [Secretary] Associate Professor (Adj) Lindsay Carey (Palliative Care Unit: La Trobe University, AU: Lindsay.Carey@latrobe.edu.au) *Dr. Valerie Adams (Food Solutions Diet Consultants, Queensland, AU: valerie@foodsolutions.com.au). * Ms. Emily Austin (Plena Healthcare, AU: Emily.Austin@plenahealthcare.com.au) *Ms. Stephanie Bates (Eastern Health, Wantirna, Victoria, AU) *Ms. Rachael Brailey (Southport Health Precinct, Southport QLD: Rachael.Brailey@health.qld.gov.au) * Dr. Christa Carey-Sargeant (Victoria Department of Education and Training, Melbourne, AU) * Ms Danielle Carey (Alexandra Hospital, Alexandra, Victoria, AU: Danielle.Carey@adh.org.au) * Ms. Alexandra Carey (Montefiore Aged Care Services, Sydney, AU: ACarey@montefiore.org.au) *Ms. Chloe Carter (West Gippsland Healthcare Group, Warragu, Victorial, AU: chloe.carter@wghg.com.au) * Ms. Beth Causa (Wollongong Speech Pathology, NSW, AU: Beth@wollongongspeech.com.au). * Dr. Laura Chahda (University of Melbourne, Victoria, AU: Laura.Chahda@unimelb.edu.au) * Ms. Sarah Chou (University of Sydney / Health NSW, AU: Sarah.Chou@health.nsw.gov.au) * Dr. Naomi Cocks (Curtin University, Western Australia, AU: Naomi.Cocks@curtin.edu.au) *Ms. Annabelle Dargeant (St. Vincent's Hospital, Victoria, AU: Annabelle.Dargeant@svha.org.au). * Ms. Lidia Davies (McKellar Centre, Barwon Health, Victoria, AU: Lidia.Davies@barwonhealth.org.au) * Ms. Brittany Fong (University of Melbourne, Victoria, AU: brit.a.fong@gmail.com) *Ms. Philippa Friary (Auckland University, Auckland, NZ: philippa.friary@auckland.ac.nz) *Ms. Asta Fung (Orange Health Service, NSW, AU: Asta.Fung@health.nsw.gov.au) * Ms. Vanessa Greenberg (Broadmeadows Hospital, Victoria, AU: Vanessa.Greenberg@nh.org.au) *Ms. Sophie Griffin (St. Vincent's Hospital, Victoria, AU: Sophie.Griffin@svha.org.au). * Ms. Sarah Hammond (Mona Vale Hospital, Northern Sydney Local Health District, AU: Sarah.Hammond@health.nsw.gov.au) * Ms. Annabel Harding (Lemongrove Community Health Centre, Penrith NSW, AU: Annabel.Harding@health.nsw.gov.au) *Ms. Bec Healy (Speech Pathology, Bunderberg Hospital Queensland, AU: Rebecca.Healy3@health.qld.gov.au). * Ms. Renee Heard (Motor Neuron Disease Clinic, Barwon Health, Geelong, Victoria, AU: Renee.Heard@barwonhealth.org.au). *Ms. Nicky Jackson (Calvary Health Care Bethlehem, Parkdale, Vic: Nicole.Jackson@calvarycare.org.au). *Ms. Ed. Jessop (Bairnsdale Regional Health Service, Victoria: ejessop24@gmail.com) * Dr. Katherine Kelly (South Western Sydney Local Health District, NSW, AU: Katherine.Kelly2@health.nsw.gov.au) * Dr. Lillian Krikheli (La Trobe University, Melbourne, AU: L.Krikheli@latrobe.edu.au) * Ms. Rebecca Lamont (Western Health, Sunshine Victoria, AU: Rebecca.Lamont@wh.org.au) *Ms. Anna Marchant (Plena Healthcare, AU: Anna.Marchant@plenahealthcare.com.au) *Mr. Yris Simon Mendoza (Calvary Health Care Kogarah, NSW, AU: Yris.Simonmendoza@health.nsw.gov.au) *Ms. Bonnie Nichols (St. Vincent's Hospital, Victoria, AU: bonnie.nichols@svha.org.au). *Ms. Morgan Perry (Ballarat Base Hospital, Ballarat, Victoria: AU). *Ms. Jennifer Petry (Neurological Rehabilitation Center, Wiesbaden, Germany, DE: Jennifer.Petry@stud.hawk.de) *Ms. Claire Radford (Children's Health, Queensland Hospital & Health Service, Queensland, AU: Claire.Radford@health.qld.gov.au) *Ms. Shanalee Perera (East Wimmera Health Service, Victoria, AU: Shanaleeperera@icloud.com) * Ass't Prof. Robin Pollens (Western Michigan University, Michigan, USA: Robin.Pollens@wmich.edu) *Ms. Oliva Purvis (Barossa Hills Fleurieu Local Health Network, South Australia: Olivia.Purvis@sa.gov.au) *Ms. Tanya Ramadan (Canterbury Hospital, New South Wales, Australia: tanya.ramadan@health.nsw.gov.au) *Ms. Amy Rosenfeld (Southern District Health Board, New Zealand: Amy.Rosenfeld@southerndhb.govt.nz) * Mr. Andy Smidt (Speech Pathology, University of Sydney, NSW, AU: Andy.Smidt@sydney.edu.au) * Ms. Rebecca Smith (Speech Pathology Department, Townsville Hospital and Health Service, AU: Rebecca.Smith@health.qld.gov.au) *Dr. Amanda Stead (School of Communication Sciences and Disorders, Pacific University, US: Amanda.Stead@pacific.edu) *Ms. Valerie Tait (Lake Macquarie Private Hospital, NSW, AU: taitv@ramsayhealth.com.au) *Ms. Esther Telfer (Flinders and Upper North Local Health Network SA Health,Government of South Australia: Esther.Telfer@sa.gov.au) *Ms. Amber Tester (Speech Pathology, Orbost Regional Health, Victoria, AU: Amber.Tester@orh.com.au) *Ms. Hanna Thompson (Casey Hospital - Monash Health, AU: Hannah.Thompson@monashhealth.org) * Prof. Travis Threats (St. Louis University, US: Travis.Threats@health.slu.edu) *Ms. Melissa Trinca (Hall and Prior Aged Care, Western Australia: mtrinca@hallprior.com.au) *Ms. Kelly Verheyen (Plena Healthcare, AU: Kelly.Verheyen@plenahealthcare.com.au) * Ms. Ashleigh Vidovich (Health, Western Australia, AU: Ashleigh.Vidovich@health.wa.gov.au) *Ms. Samantha White (Queensland Children’s Hospital, South Brisbane, AU: Samantha.White2@health.qld.gov.au). * Ms. Catherin Wilton (Yooralla, Allied Services and Wellbeing – North and East, Melbourne, AU: Catherine.Wilton@yooralla.com.au). *Ms. Ciara Winstanley (Tablelands Allied Health, Cairns, Queensland, AU: Ciara.Winstanley@health.qld.gov.au) *Ms. Rachel Wong (Latrobe Regional Hospital, Victoria, AU: RWong@lrh.com.au). * [Palliative Care Advisor: Professor Bruce Rumbold,OAM: (Adjunct: Palliative Care Unit, La Trobe University] == SLP-PalCare-SIG Activities == [[File:Dr. Laura Chahda.jpg|thumb|'''Dr. Laura Chahda'''. Publicatons Award for Research into SLPs and Adult Palliative Care in Australia]] === ''(1) Annual Meeting: SPA Conference 2022 (refer 3. below)'' === See below for recommended workshop pre-reading: === ''(2)'' ''National'' ''SPA Conference 2022: 'Beyond Borders' 22 - 25'' MAY 2022 (Melbourne) === '''SPA-PalCareSIG 2022: Congratulations to Dr. Laura Chahda who was presented with the Taylor & Francis / International Journal of Speech, Language and Hearing Best Publication Award for her research into Adult Palliative Care and SLPs in Australia. If you would like to read the article please see the link below:''' Chahda, L., Carey, L. B., Mathisen, B. A., & Threats, T. (2021). Speech-language pathologists and adult palliative care in Australia. ''International Journal of Speech-Language Pathology'', ''23''(1), 57-69. https://doi.org/10.1080/17549507.2020.1730966 === (3'')'' ''National'' ''SPA Conference 2023: 21 - 24'' MAY 2023 (Hobart) === https://www.emedevents.com/c/medical-conferences-2023/speech-pathology-australia-spa-national-conference-2023 Hotel Grand Chancellor, Hobart Tasmania, Australia: https://www.grandchancellorhotels.com/hotel-grand-chancellor-hobart === ''(4)'' ''ASHA Upcoming Events:'' https://www.asha.org/slp/slp-calendar/ === === ''(5'') 7th International Public Health Palliative Care Conference (2022): Bruges, Belgium. === ====== ''"End of Life Research, Public Health and Palliative Care''' Further details to be provided. [http://phpci.info/7th-international-conference <nowiki>[2]</nowiki>] ====== == SLP-PalCare-SIG Communications / Twitter == For regular updates, please join 'follow' our Twitter Account: https://twitter.com/SigSlp == SLP-PalCare-SIG Book and Chapter == * Mathisen, B.A. & Carey, L.B. (2023: <u>In press</u>). ''Speech-Language Pathology and Palliative Care''. London: SAGE Publishers. * Mathisen, B.A. & Threats, T. (2018). Speech-Language Pathology and Spiritual Care. In Carey, L.B. & Mathisen, B.A. (2020). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html<nowiki/> Carey, L.B. & Mathisen, B.A. (2018). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. [https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.htm] ''['''This book is free to all SPA-PalCare-SIG members; please contact the Secretary for your free copy]''''' == Recommended References == The following sources (in alphabetical order) are recommended reading regarding the role of SLPs in Palliative Care: * Chahda, L., Carey, L. B., Mathisen, B. A., & Threats, T. (2020). Speech-language pathologists and adult palliative care in Australia. [[doi:10.1080/17549507.2020.1730966|''International Journal of Speech-Language Pathology'']], 23 (1), 57-69. * Chahda, L., Dell’Oro, H., Skeat, J. & Keage, M. (2022). Learning at end of Life Preparedness of speech language pathology graduates to work in palliative care. ''Journal of Clinical Practice in Speech-Language Pathology''. 24 (2), 77-79. [JCPSLP availalbe via request to author] * Chahda, L., Mathisen, B. A., & Carey, L. B. (2017). The role of speech-language pathologists in adult palliative care. [[doi:10.1080/17549507.2016.1241301|''International Journal of Speech-Language Pathology'']], 19(1), 58-68. *Collins, C.A. (2022). There’s this big fear around palliative care because it’s connected to death and dying’: A qualitative exploration of the perspectives of undergraduate students on the role of the speech and language therapist in palliative care. ''Palliative Medicine''. 36(1), 171 –180. https://doi.org/10.1177/02692163211050818 * DeZeeuw, K., & Lalonde Myers, E. (2020). The Role of Speech-Language Pathologists in Medical Assistance in Dying: Canadian Experience to Inform Clinical Practice. ''Canadian Journal of Speech-Language Pathology & Audiology'', ''44''(2).https://cjslpa.ca/detail.php?ID=1259&lang=en *Fong, R., Tsai, C., Wong, H., Yiu, O., & Luk, J. K. H. (2019). Speech therapy in palliative care and comfort feeding: Current practice and way ahead. ''Asian Journal of Gerontolology and Geriatrics'', ''142'', 61-68. https://doi.org/10.12809/ajgg-2018-330-oa *Hanna, E., & Joel, A. (2005). End-of-Life Decision Making, Quality of Life, Enteral Feeding, and the Speech-Language Pathologist. ''Perspectives on Swallowing and Swallowing Disorders (Dysphagia)'', ''14''(3), 13-18. https://pubs.asha.org/doi/full/10.1044/sasd14.3.13 * Hawksley, R., Ludlow, F., Buttimer, H., & Bloch, S. (2017). Communication disorders in palliative care: Investigating the views, attitudes and beliefs of speech and language therapists. ''International Journal of Palliative Nursing'', 23, 543–551. doi: 10.12968/ijpn.2017.23.11.543. * Gravier, S. (2019). Palliative care and how evidence supports speech pathologists who care people at end of life. ''Speech Pathology Australia'' ''Speak Out''. June, p. 20-21. * Kelly, K., Cumming, S., Corry, A., Gilsenan, K., Tamone, C., Vella, K., & Bogaardt, H. (2016). The role of speech-language pathologists in palliative care: Where are we now? A review of the literature. ''Progress in Palliative Care'', 24(6), 315-323. * Kelly, K., Cumming, S., Kenny, B., Smith-Merry, J., & Bogaardt, H. (2018). Getting comfortable with “comfort feeding”: An exploration of legal and ethical aspects of the Australian speech-language pathologist’s role in palliative dysphagia care. [https://doi.org/10.1080/17549507.2018.1448895 ''International Journal of Speech-Language Pathology''], 20(3), 371-379. * Krikheli, L., Mathisen, B. A., & Carey, L. B. (2018). Speech–language pathology in paediatric palliative care: A scoping review of role and practice. [[doi:10.1080/17549507.2017.1337225|''International Journal of Speech-Language Pathology'']], 20(5), 541-553. * Krikheli, L., Carey, L. B., Mathisen, B. A., Erickson, S., & Carey-Sargeant, C. (2018). Recommendations for Speech-Language Pathologists in Paediatric Palliative Care Teams (ReSP3CT):  A modified Delphi study protocol. ''BMJ Supportive & Palliative Care'', ''Online First'', 1-7. doi:[https://spcare.bmj.com/content/early/2018/12/04/bmjspcare-2018-001667 10.1136/bmjspcare-2018-001667] * Krikheli, L., Carey, L. B., Erickson, S., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Recommendations for Speech-Language Pathologists in Paediatric Palliative Care (ReSP3CT): An International Modified Delphi Study. ''International Journal of Speech Language Pathology, Online: : https://doi.org/10.1080/17549507.2020.1866073'' * Krikheli, L., Erickson, S., Carey, L. B., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Perspectives of speech and language therapists in paediatric palliative care: An international exploratory study. ''International Journal of Language & Communication Disorders''. Online:https://doi.org/10.1111/1460-6984.12539 * Krikheli, L., Erickson, S., Carey, L. B., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Speech-Language Pathologists in Pediatric Palliative Care: An International Study of Perceptions and Experiences. ''American Journal of Speech-Language Pathology, 30(1), 150-168:'' https://doi.org/10.1044/2020_AJSLP-20-00090 *Mahendra, N., & Alonso, M. (2020). Knowledge of palliative care and advance directives among speech–language pathology students. ''Topics in Language Disorders'', ''40''(3), 248-263. doi: [https://journals.lww.com/topicsinlanguagedisorders/Fulltext/2020/07000/Knowledge_of_Palliative_Care_and_Advance.4.aspx?context=LatestArticles&casa_token=ShEWF4FPHaYAAAAA:GonKQr-DILgbKQ-X_j7r-nWZ15vUBTHWLjiumoxF9gpCErnQB_JlMyfmBo8AQwNDWYp30IHCdvuaW5ppDi11OFsqkTQMFBHl 10.1097/TLD.0000000000000224] * Mathisen, B., Carey, L. B., Carey-Sargeant, C. L., Webb, G., Millar, C., & Krikheli, L. (2015). Religion, spirituality and speech-language pathology: A viewpoint for ensuring patient-centred holistic care. [https://link.springer.com/article/10.1007/s10943-015-0001-1 ''Journal of Religion and Health''], 54(6), 2309–2323. * Mathisen, B.A. & Threats, T. (2018). Speech-Language Pathology and Spiritual Care. In Carey, L.B. & Mathisen, B.A. (2020). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html *Mathisen, B.A., Yates, P., Crofts, P. (2010). Palliative care curriculum for speech-language pathology students. International Journal of Language and Communication Disorders. 46 (3), 273–285. https://doi.org/10.3109/13682822.2010.495739 * Martins, S., & Castro Alves, S. (2017). Speech Therapy in Palliative Care—Portuguese Perspective. ''Journal of Palliative Medicine'', ''20''(1), 7-7. https://doi.org/10.1089/jpm.2016.0407 * O'Reilly, A.C. & Walshe, M. (2015). Perspectives on the role of the speech and language therapist in palliative care: An international survey. ''Palliative Medicine'', 29(8), 756-761. https://doi.org/10.1177/0269216315575678 *Pascoe, A., Breen, L.J., & Cocks, N. (2018). What is needed to prepare speech pathologists to work in palliative care?. ''International Journal of Language and Communication Disorders'', 53(3), 542-549. https://doi.org/10.1111/1460-6984.12367 *Pollens, R., Chahda, L., Freeman-Sanderson, A., Lalonde Myers, E., & Mathison, B. (2021). Supporting Crucial Conversations: Speech–Language Pathology Intervention in Palliative End-of-Life Care. ''Journal of Palliative Medicine'', ''24''(7), 969-970. https://doi.org/10.1089/jpm.2021.0134 * Pollens, R. (2020). Facilitating Client Ability to Communicate in Palliative End-of-Life Care: Impact of Speech-Language Pathologists. ''Topics in Language Disorders'', ''40 (3)'' , 264-277. https://doi.org/10.1097/TLD.0000000000000220 * Pollens, R. (2012). Integrating speech-language pathology services in palliative end-of-life care. ''Topics in Language Disorders'', 32, 137–148. doi:10.1097/TLD.0b013e3182543533. * Pollens, R. (2004). Role of the speech-language pathologist in palliative hospice care. ''Journal of Palliative Medicine'', 7, 694–702. doi:10.1089/jpm.2004.7.694. *Stead, A., Dirks, K., Fryer, M., & Wong, S. (2020). Training Future Speech–Language Pathologists for Work in End-of-Life and Palliative Care. ''Topics in Language Disorders'', ''40''(3), 233-247. [https://journals.lww.com/topicsinlanguagedisorders/Fulltext/2020/07000/Training_Future_Speech_Language_Pathologists_for.3.aspx?context=LatestArticles&casa_token=xhOJ4QNeOYAAAAAA:dlnCDcLnUIlV5NHlSvnUFlQHlVs-M04yLcMme_t0-wlerM-NuTYUH23RYeDejfn-zLa17zoU-ri-BbVxoZ9aq07oTtmzhQ69 doi: 10.1097/TLD.0000000000000219] aputvjpsro3ri1whuud7o5ppjhjbfr8 2408246 2408240 2022-07-21T01:38:43Z LinzCarey 2848224 Correction wikitext text/x-wiki == Speech-Language Pathology in Palliative Care – Special Interest Group == __TOC__ == Introduction == Speech-Language Pathology (SLP) in Palliative Care (PalCare) is a new and developing area of specialty which aims to provide appropriate SLP practice within palliative and end-of-life care services. While the profession of [[:w:Speech-language pathology|speech-language pathology/speech therapy]] has been in existence since the turn of the 20th Century, and [[:w:Palliative care|palliative care]] has been practiced for centuries (in one form or another), nevertheless, the combination of the two disciplinary areas intersecting has often been intermittent and highly dependent upon a specific institutional context, rather than being systematically endorsed by any government regulations or professional association clinical practice guidelines (CPGs). == SLP-PalCare Focus == Speech-Language Pathology in Palliative Care Special Interest Group has a primary focus upon ten major areas in order to support SLPs in Palliative Care and redress the lack of SLP CPGs in Palliative Care:[https://www.tandfonline.com/doi/full/10.1080/17549507.2020.1730966 Chahda et al (2020)] # Encouraging, developing and/or conducting ongoing research and creating resources for SLPs working in Palliative Care. # Educating health professions about the role of SLPs in PalCare. # Establishing referral procedures for SLP intervention within PalCare. # Integrating PalCare within SLP tertiary education. # Promoting the education, consultation, supervision and mentoring of SLPs new to PalCare. # Incorporating SLP observations and interventions into the overall multi-disciplinary/palliative care team goals. # Focussing PalCare assessment and therapy to include both cognitive-communication and swallowing interventions. # Integration of SLPs as a part of a practical, consultative and holistic PalCare approach. # Encouraging professional self-care consideration for SLPs working in PalCare. # The development of uniform SLP-PalCare CPGs == Research and Future Development == Based upon the findings of an increasing number of researchers [for example see the reviews of [https://doi.org/10.1080/17549507.2016.1241301 Chahda et al (2017)] and [https://doi.org/10.1080/17549507.2017.1337225 Krikheli et al (2018)] there is clearly a need for further research and increased scope of practice accompanied by the development of SLP clinical practice guidelines so as to enhance the multidisciplinary and holistic collaboration of SLPs within Palliative Care contexts. ==== CURRENT RESEARCH (2022) ==== '''"Identifing facilitators and barriers to successful speech pathology student placements in the palliative care setting"''' '''Time frame:'''  May to August 2022 '''Survey:''' Completed. '''Focus Groups''': Completed. '''Interviews:''' Planning This project is being completed by researchers from The University of Melbourne and Deakin University. * Dr Laura Chahda (Email: laura.chahda@unimelb.edu.au) * Dr Megan Keage (Email: megan.keage@unimelb.edu.au) * Ms Hayley Dell’Oro (Email: hayley.delloro@unimelb.edu) * Dr Jemma Skeat (Email: jemma.skeat@deakin.edu.au) '''"The PCC4U (Palliative Care Curriculum for Undergraduates"''': https://pcc4u.org.au/) assists in providing resources for the trainng of undergradutes in palliative care and provides a number of resources incuding vdieo case studies: (access via: https://www.youtube.com/user/PCC4UProject/playlists) one of which mentions SLPs: (https://pcc4u.org.au/learning/modules/module4/m4_section3/m4_activity8/). == SLP-PalCare-SIG Representatives & Membership == To achieve the objective foci of SLPs within Palliative Care (as noted above) the formation of the 'Speech-Language Pathology and Palliative Care Special Interest Group' (SLP-PalCare-SIG) has been listed by [https://www.speechpathologyaustralia.org.au/SPAweb/Resources_For_Speech_Pathologists/Non_SPA_Resources/Special_Interest_Groups/SPAweb/Resources_for_Speech_Pathologists/Non_SPA_Resources/Special_Interest_Groups.aspx?hkey=c1a0adee-4577-45e1-9c1e-31ee203f2789 '''Speech Pathology Australia'''] (SPA) and currently involves representatives from a number of universities and clinical practices. There is no fee to be a member of the SLP-PalCare-SIG. Please email the secretary if you are interested in joining. ''SLP-PalCare-SIG Members (Alphabetical by Surname):'' * [Chairperson] Professor. Bernice Mathisen (University of Southern Queensland, AU: Bernice.Mathisen@usq.edu.au) * [Secretary] Associate Professor (Adj) Lindsay Carey (Palliative Care Unit: La Trobe University, AU: Lindsay.Carey@latrobe.edu.au) *Dr. Valerie Adams (Food Solutions Diet Consultants, Queensland, AU: valerie@foodsolutions.com.au). * Ms. Emily Austin (Plena Healthcare, AU: Emily.Austin@plenahealthcare.com.au) *Ms. Stephanie Bates (Eastern Health, Wantirna, Victoria, AU) *Ms. Rachael Brailey (Southport Health Precinct, Southport QLD: Rachael.Brailey@health.qld.gov.au) * Dr. Christa Carey-Sargeant (Victoria Department of Education and Training, Melbourne, AU) * Ms Danielle Carey (Alexandra Hospital, Alexandra, Victoria, AU: Danielle.Carey@adh.org.au) * Ms. Alexandra Carey (Montefiore Aged Care Services, Sydney, AU: ACarey@montefiore.org.au) *Ms. Chloe Carter (West Gippsland Healthcare Group, Warragu, Victorial, AU: chloe.carter@wghg.com.au) * Ms. Beth Causa (Wollongong Speech Pathology, NSW, AU: Beth@wollongongspeech.com.au). * Dr. Laura Chahda (University of Melbourne, Victoria, AU: Laura.Chahda@unimelb.edu.au) * Ms. Sarah Chou (University of Sydney / Health NSW, AU: Sarah.Chou@health.nsw.gov.au) * Dr. Naomi Cocks (Curtin University, Western Australia, AU: Naomi.Cocks@curtin.edu.au) *Ms. Annabelle Dargeant (St. Vincent's Hospital, Victoria, AU: Annabelle.Dargeant@svha.org.au). * Ms. Lidia Davies (McKellar Centre, Barwon Health, Victoria, AU: Lidia.Davies@barwonhealth.org.au) * Ms. Brittany Fong (University of Melbourne, Victoria, AU: brit.a.fong@gmail.com) *Ms. Philippa Friary (Auckland University, Auckland, NZ: philippa.friary@auckland.ac.nz) *Ms. Asta Fung (Orange Health Service, NSW, AU: Asta.Fung@health.nsw.gov.au) * Ms. Vanessa Greenberg (Broadmeadows Hospital, Victoria, AU: Vanessa.Greenberg@nh.org.au) *Ms. Sophie Griffin (St. Vincent's Hospital, Victoria, AU: Sophie.Griffin@svha.org.au). * Ms. Sarah Hammond (Mona Vale Hospital, Northern Sydney Local Health District, AU: Sarah.Hammond@health.nsw.gov.au) * Ms. Annabel Harding (Lemongrove Community Health Centre, Penrith NSW, AU: Annabel.Harding@health.nsw.gov.au) *Ms. Bec Healy (Speech Pathology, Bunderberg Hospital Queensland, AU: Rebecca.Healy3@health.qld.gov.au). * Ms. Renee Heard (Motor Neuron Disease Clinic, Barwon Health, Geelong, Victoria, AU: Renee.Heard@barwonhealth.org.au). *Ms. Nicky Jackson (Calvary Health Care Bethlehem, Parkdale, Vic: Nicole.Jackson@calvarycare.org.au). *Ms. Ed. Jessop (Bairnsdale Regional Health Service, Victoria: ejessop24@gmail.com) * Dr. Katherine Kelly (South Western Sydney Local Health District, NSW, AU: Katherine.Kelly2@health.nsw.gov.au) * Dr. Lillian Krikheli (La Trobe University, Melbourne, AU: L.Krikheli@latrobe.edu.au) * Ms. Rebecca Lamont (Western Health, Sunshine Victoria, AU: Rebecca.Lamont@wh.org.au) *Ms. Anna Marchant (Plena Healthcare, AU: Anna.Marchant@plenahealthcare.com.au) *Mr. Yris Simon Mendoza (Calvary Health Care Kogarah, NSW, AU: Yris.Simonmendoza@health.nsw.gov.au) *Ms. Bonnie Nichols (St. Vincent's Hospital, Victoria, AU: bonnie.nichols@svha.org.au). *Ms. Morgan Perry (Ballarat Base Hospital, Ballarat, Victoria: AU). *Ms. Jennifer Petry (Neurological Rehabilitation Center, Wiesbaden, Germany, DE: Jennifer.Petry@stud.hawk.de) *Ms. Claire Radford (Children's Health, Queensland Hospital & Health Service, Queensland, AU: Claire.Radford@health.qld.gov.au) *Ms. Shanalee Perera (East Wimmera Health Service, Victoria, AU: Shanaleeperera@icloud.com) * Ass't Prof. Robin Pollens (Western Michigan University, Michigan, USA: Robin.Pollens@wmich.edu) *Ms. Oliva Purvis (Barossa Hills Fleurieu Local Health Network, South Australia: Olivia.Purvis@sa.gov.au) *Ms. Tanya Ramadan (Canterbury Hospital, New South Wales, Australia: tanya.ramadan@health.nsw.gov.au) *Ms. Amy Rosenfeld (Southern District Health Board, New Zealand: Amy.Rosenfeld@southerndhb.govt.nz) * Mr. Andy Smidt (Speech Pathology, University of Sydney, NSW, AU: Andy.Smidt@sydney.edu.au) * Ms. Rebecca Smith (Speech Pathology Department, Townsville Hospital and Health Service, AU: Rebecca.Smith@health.qld.gov.au) *Dr. Amanda Stead (School of Communication Sciences and Disorders, Pacific University, US: Amanda.Stead@pacific.edu) *Ms. Valerie Tait (Lake Macquarie Private Hospital, NSW, AU: taitv@ramsayhealth.com.au) *Ms. Esther Telfer (Flinders and Upper North Local Health Network SA Health,Government of South Australia: Esther.Telfer@sa.gov.au) *Ms. Amber Tester (Speech Pathology, Orbost Regional Health, Victoria, AU: Amber.Tester@orh.com.au) *Ms. Hanna Thompson (Casey Hospital - Monash Health, AU: Hannah.Thompson@monashhealth.org) * Prof. Travis Threats (St. Louis University, US: Travis.Threats@health.slu.edu) *Ms. Melissa Trinca (Hall and Prior Aged Care, Western Australia: mtrinca@hallprior.com.au) *Ms. Kelly Verheyen (Plena Healthcare, AU: Kelly.Verheyen@plenahealthcare.com.au) * Ms. Ashleigh Vidovich (Health, Western Australia, AU: Ashleigh.Vidovich@health.wa.gov.au) *Ms. Samantha White (Queensland Children’s Hospital, South Brisbane, AU: Samantha.White2@health.qld.gov.au). * Ms. Catherin Wilton (Yooralla, Allied Services and Wellbeing – North and East, Melbourne, AU: Catherine.Wilton@yooralla.com.au). *Ms. Ciara Winstanley (Tablelands Allied Health, Cairns, Queensland, AU: Ciara.Winstanley@health.qld.gov.au) *Ms. Rachel Wong (Latrobe Regional Hospital, Victoria, AU: RWong@lrh.com.au). * [Palliative Care Advisor: Professor Bruce Rumbold,OAM: (Adjunct: Palliative Care Unit, La Trobe University] == SLP-PalCare-SIG Activities == [[File:Dr. Laura Chahda.jpg|thumb|'''Dr. Laura Chahda'''. Publicatons Award for Research into SLPs and Adult Palliative Care in Australia]] === ''(1) Annual Meeting: SPA Conference 2022 (refer 3. below)'' === See below for recommended workshop pre-reading: === ''(2)'' ''National'' ''SPA Conference 2022: 'Beyond Borders' 22 - 25'' MAY 2022 (Melbourne) === '''SPA-PalCareSIG 2022: Congratulations to Dr. Laura Chahda who was presented with the Taylor & Francis / International Journal of Speech, Language and Hearing Best Publication Award for her research into Adult Palliative Care and SLPs in Australia. If you would like to read the article please see the link below:''' Chahda, L., Carey, L. B., Mathisen, B. A., & Threats, T. (2021). Speech-language pathologists and adult palliative care in Australia. ''International Journal of Speech-Language Pathology'', ''23''(1), 57-69. https://doi.org/10.1080/17549507.2020.1730966 === (3'')'' ''National'' ''SPA Conference 2023: 21 - 24'' MAY 2023 (Hobart) === https://www.emedevents.com/c/medical-conferences-2023/speech-pathology-australia-spa-national-conference-2023 Hotel Grand Chancellor, Hobart Tasmania, Australia: https://www.grandchancellorhotels.com/hotel-grand-chancellor-hobart === ''(4)'' ''ASHA Upcoming Events:'' https://www.asha.org/slp/slp-calendar/ === === ''(5'') 7th International Public Health Palliative Care Conference (2022): Bruges, Belgium. === ====== ''"End of Life Research, Public Health and Palliative Care''' Further details to be provided. [http://phpci.info/7th-international-conference <nowiki>[2]</nowiki>] ====== == SLP-PalCare-SIG Communications / Twitter == For regular updates, please join 'follow' our Twitter Account: https://twitter.com/SigSlp == SLP-PalCare-SIG Book and Chapter == * Mathisen, B.A. & Carey, L.B. (2023: <u>In press</u>). ''Speech-Language Pathology and Palliative Care''. London: SAGE Publishers. * Mathisen, B.A. & Threats, T. (2018). Speech-Language Pathology and Spiritual Care. In Carey, L.B. & Mathisen, B.A. (2020). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html<nowiki/> Carey, L.B. & Mathisen, B.A. (2018). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. [https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.htm] ''['''This book is free to all SPA-PalCare-SIG members; please contact the Secretary for your free copy]''''' == Recommended References == The following sources (in alphabetical order) are recommended reading regarding the role of SLPs in Palliative Care: * Chahda, L., Carey, L. B., Mathisen, B. A., & Threats, T. (2020). Speech-language pathologists and adult palliative care in Australia. [[doi:10.1080/17549507.2020.1730966|''International Journal of Speech-Language Pathology'']], 23 (1), 57-69. * Chahda, L., Dell’Oro, H., Skeat, J. & Keage, M. (2022). Learning at end of Life Preparedness of speech language pathology graduates to work in palliative care. ''Journal of Clinical Practice in Speech-Language Pathology''. 24 (2), 77-79. [JCPSLP article available via SPA or author] * Chahda, L., Mathisen, B. A., & Carey, L. B. (2017). The role of speech-language pathologists in adult palliative care. [[doi:10.1080/17549507.2016.1241301|''International Journal of Speech-Language Pathology'']], 19(1), 58-68. *Collins, C.A. (2022). There’s this big fear around palliative care because it’s connected to death and dying’: A qualitative exploration of the perspectives of undergraduate students on the role of the speech and language therapist in palliative care. ''Palliative Medicine''. 36(1), 171 –180. https://doi.org/10.1177/02692163211050818 * DeZeeuw, K., & Lalonde Myers, E. (2020). The Role of Speech-Language Pathologists in Medical Assistance in Dying: Canadian Experience to Inform Clinical Practice. ''Canadian Journal of Speech-Language Pathology & Audiology'', ''44''(2).https://cjslpa.ca/detail.php?ID=1259&lang=en *Fong, R., Tsai, C., Wong, H., Yiu, O., & Luk, J. K. H. (2019). Speech therapy in palliative care and comfort feeding: Current practice and way ahead. ''Asian Journal of Gerontolology and Geriatrics'', ''142'', 61-68. https://doi.org/10.12809/ajgg-2018-330-oa *Hanna, E., & Joel, A. (2005). End-of-Life Decision Making, Quality of Life, Enteral Feeding, and the Speech-Language Pathologist. ''Perspectives on Swallowing and Swallowing Disorders (Dysphagia)'', ''14''(3), 13-18. https://pubs.asha.org/doi/full/10.1044/sasd14.3.13 * Hawksley, R., Ludlow, F., Buttimer, H., & Bloch, S. (2017). Communication disorders in palliative care: Investigating the views, attitudes and beliefs of speech and language therapists. ''International Journal of Palliative Nursing'', 23, 543–551. doi: 10.12968/ijpn.2017.23.11.543. * Gravier, S. (2019). Palliative care and how evidence supports speech pathologists who care people at end of life. ''Speech Pathology Australia'' ''Speak Out''. June, p. 20-21. * Kelly, K., Cumming, S., Corry, A., Gilsenan, K., Tamone, C., Vella, K., & Bogaardt, H. (2016). The role of speech-language pathologists in palliative care: Where are we now? A review of the literature. ''Progress in Palliative Care'', 24(6), 315-323. * Kelly, K., Cumming, S., Kenny, B., Smith-Merry, J., & Bogaardt, H. (2018). Getting comfortable with “comfort feeding”: An exploration of legal and ethical aspects of the Australian speech-language pathologist’s role in palliative dysphagia care. [https://doi.org/10.1080/17549507.2018.1448895 ''International Journal of Speech-Language Pathology''], 20(3), 371-379. * Krikheli, L., Mathisen, B. A., & Carey, L. B. (2018). Speech–language pathology in paediatric palliative care: A scoping review of role and practice. [[doi:10.1080/17549507.2017.1337225|''International Journal of Speech-Language Pathology'']], 20(5), 541-553. * Krikheli, L., Carey, L. B., Mathisen, B. A., Erickson, S., & Carey-Sargeant, C. (2018). Recommendations for Speech-Language Pathologists in Paediatric Palliative Care Teams (ReSP3CT):  A modified Delphi study protocol. ''BMJ Supportive & Palliative Care'', ''Online First'', 1-7. doi:[https://spcare.bmj.com/content/early/2018/12/04/bmjspcare-2018-001667 10.1136/bmjspcare-2018-001667] * Krikheli, L., Carey, L. B., Erickson, S., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Recommendations for Speech-Language Pathologists in Paediatric Palliative Care (ReSP3CT): An International Modified Delphi Study. ''International Journal of Speech Language Pathology, Online: : https://doi.org/10.1080/17549507.2020.1866073'' * Krikheli, L., Erickson, S., Carey, L. B., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Perspectives of speech and language therapists in paediatric palliative care: An international exploratory study. ''International Journal of Language & Communication Disorders''. Online:https://doi.org/10.1111/1460-6984.12539 * Krikheli, L., Erickson, S., Carey, L. B., Carey‐Sargeant, C. L., & Mathisen, B. A. (2020). Speech-Language Pathologists in Pediatric Palliative Care: An International Study of Perceptions and Experiences. ''American Journal of Speech-Language Pathology, 30(1), 150-168:'' https://doi.org/10.1044/2020_AJSLP-20-00090 *Mahendra, N., & Alonso, M. (2020). Knowledge of palliative care and advance directives among speech–language pathology students. ''Topics in Language Disorders'', ''40''(3), 248-263. doi: [https://journals.lww.com/topicsinlanguagedisorders/Fulltext/2020/07000/Knowledge_of_Palliative_Care_and_Advance.4.aspx?context=LatestArticles&casa_token=ShEWF4FPHaYAAAAA:GonKQr-DILgbKQ-X_j7r-nWZ15vUBTHWLjiumoxF9gpCErnQB_JlMyfmBo8AQwNDWYp30IHCdvuaW5ppDi11OFsqkTQMFBHl 10.1097/TLD.0000000000000224] * Mathisen, B., Carey, L. B., Carey-Sargeant, C. L., Webb, G., Millar, C., & Krikheli, L. (2015). Religion, spirituality and speech-language pathology: A viewpoint for ensuring patient-centred holistic care. [https://link.springer.com/article/10.1007/s10943-015-0001-1 ''Journal of Religion and Health''], 54(6), 2309–2323. * Mathisen, B.A. & Threats, T. (2018). Speech-Language Pathology and Spiritual Care. In Carey, L.B. & Mathisen, B.A. (2020). ''Spiritual Care for Allied Health Practice: A person-centered approach''. London: Jessica Kingsley Press. https://www.jkp.com/aus/spiritual-care-for-allied-health-practice.html *Mathisen, B.A., Yates, P., Crofts, P. (2010). Palliative care curriculum for speech-language pathology students. International Journal of Language and Communication Disorders. 46 (3), 273–285. https://doi.org/10.3109/13682822.2010.495739 * Martins, S., & Castro Alves, S. (2017). Speech Therapy in Palliative Care—Portuguese Perspective. ''Journal of Palliative Medicine'', ''20''(1), 7-7. https://doi.org/10.1089/jpm.2016.0407 * O'Reilly, A.C. & Walshe, M. (2015). Perspectives on the role of the speech and language therapist in palliative care: An international survey. ''Palliative Medicine'', 29(8), 756-761. https://doi.org/10.1177/0269216315575678 *Pascoe, A., Breen, L.J., & Cocks, N. (2018). What is needed to prepare speech pathologists to work in palliative care?. ''International Journal of Language and Communication Disorders'', 53(3), 542-549. https://doi.org/10.1111/1460-6984.12367 *Pollens, R., Chahda, L., Freeman-Sanderson, A., Lalonde Myers, E., & Mathison, B. (2021). Supporting Crucial Conversations: Speech–Language Pathology Intervention in Palliative End-of-Life Care. ''Journal of Palliative Medicine'', ''24''(7), 969-970. https://doi.org/10.1089/jpm.2021.0134 * Pollens, R. (2020). Facilitating Client Ability to Communicate in Palliative End-of-Life Care: Impact of Speech-Language Pathologists. ''Topics in Language Disorders'', ''40 (3)'' , 264-277. https://doi.org/10.1097/TLD.0000000000000220 * Pollens, R. (2012). Integrating speech-language pathology services in palliative end-of-life care. ''Topics in Language Disorders'', 32, 137–148. doi:10.1097/TLD.0b013e3182543533. * Pollens, R. (2004). Role of the speech-language pathologist in palliative hospice care. ''Journal of Palliative Medicine'', 7, 694–702. doi:10.1089/jpm.2004.7.694. *Stead, A., Dirks, K., Fryer, M., & Wong, S. (2020). Training Future Speech–Language Pathologists for Work in End-of-Life and Palliative Care. ''Topics in Language Disorders'', ''40''(3), 233-247. [https://journals.lww.com/topicsinlanguagedisorders/Fulltext/2020/07000/Training_Future_Speech_Language_Pathologists_for.3.aspx?context=LatestArticles&casa_token=xhOJ4QNeOYAAAAAA:dlnCDcLnUIlV5NHlSvnUFlQHlVs-M04yLcMme_t0-wlerM-NuTYUH23RYeDejfn-zLa17zoU-ri-BbVxoZ9aq07oTtmzhQ69 doi: 10.1097/TLD.0000000000000219] phoaic9ouezoc73a3zqbzkdh58z77rs 0 262696 2408234 2405755 2022-07-20T23:10:44Z Evolution and evolvability 922352 /* Accepted articles */ links wikitext text/x-wiki <noinclude>{{WikiJ top menu}}</noinclude> This is a summary of [[WikiJournal User Group/Editorial guidelines|WikiJournal's editorial guidelines]] for [[WikiJournal User Group/Technical editors|technical editors of WikiJournal]], outlining key processes. == Relevant links == *'''[[WikiJournal User Group/Technical editors/tasks|Current task list]]''' *'''[https://groups.google.com/g/wikijournal-technical Passwords and confidential links]''' * [[WikiJournal User Group/Editorial guidelines|Full editorial process guidelines]] * [[WikiJournal User Group/Editorial guidelines/Message templates|Template emails]], these are only suggestions so you are welcome to adapt whenever relevant * Useful emails: ** WJMboard@googlegroups.com - 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If article intended for Wikipedia-integration, copy contents over to corresponding Wikipedia page (or ask authors) and add template to refs section ([[WikiJournal User Group/Editorial guidelines#As_content|link]]) #*if in doubt, check ‘Author declaration form responses’ ([https://groups.google.com/g/wikijournal-technical confidential link listed here]) # Format and upload the PDF (steps below) === PDF formatting === {{#lsth:WikiJournal User Group/Editorial guidelines|Creation of PDF files}} === PDF upload === {{#lsth:WikiJournal User Group/Editorial guidelines|Uploading PDF files to the journal}} # Update the published article's wikidata item ([[WikiJournal User Group/Editorial guidelines#Updating published article metadata in wikidata|info to add]]) ==Further reading== *[[WikiJournal User Group/Technical editors]], for a general description about this editor category kl4rudb0r2yty0gdo7fu6epsd2sk0um 0 263444 2408184 2407945 2022-07-20T15:47:29Z Scogdill 1331941 wikitext text/x-wiki == Also Known As == *Louise, Duchess of Devonshire *Louisa, Duchess of Manchester *Luise Friederike August Gräfin von Alten *Louisa Montagu *Louise Cavendish *The Double Duchess == Acquaintances, Friends and Enemies == === Friends === *[[Social Victorians/People/Albert Edward, Prince of Wales | Albert Edward, Prince of Wales]] (beginning about 1852) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], Lord Hartington (later 8th Duke of Devonshire) *Daisy, Lady Warwick *Lady Mayoress, Mrs. Benjamin Samuel Faudel-Phillips, 2nd Baronet,<ref>{{Cite journal|date=2020-08-25|title=Faudel-Phillips baronets|url=https://en.wikipedia.org/w/index.php?title=Faudel-Phillips_baronets&oldid=974879290|journal=Wikipedia|language=en}}</ref> presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4">"The Queen's Drawing Room" ''Morning Post'' 25 February 1897 Thursday: 5 [of 10], Col. 5a–7b [of 8]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970225/047/0005.</ref>{{rp|p. 5, Col. 6c}} *Mrs. J. E. Mellor, presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4" />{{rp|p. 5, Col. 6c}} === Enemies === * Consuelo, Duchess of Marlborough (at least, in 1901)<ref name=":1">Murphy, Sophia. ''The Duchess of Devonshire's Ball''. London: Sidgwick & Jackson, 1984.</ref>{{rp|pp. 31–32}} == Organizations == == Timeline == '''1852 July 22''', Luise Friederike Auguste Gräfin von Alten and William Drogo Montagu married.<ref name=":2">"Luise Friederike Auguste Gräfin von Alten." {{Cite web|url=http://www.thepeerage.com/p10947.htm#i109469|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1863, early, or late 1862''', Louise and Spencer Compton Cavendish began a relationship.<ref name=":1" />{{rp|p. 26}} '''1873 December 10''', Mary Louise Elizabeth Montagu (daughter) and William Douglas-Hamilton married. '''1876 May 22''', Consuelo Iznaga y Clement and George Victor Drogo Montagu (son) married in Grace Church, New York City.<ref>{{Cite journal|date=2020-08-24|title=George Montagu, 8th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=George_Montagu,_8th_Duke_of_Manchester&oldid=974659520|journal=Wikipedia|language=en}}</ref><ref>{{Cite journal|date=2020-07-27|title=Consuelo Montagu, Duchess of Manchester|url=https://en.wikipedia.org/w/index.php?title=Consuelo_Montagu,_Duchess_of_Manchester&oldid=969888488|journal=Wikipedia|language=en}}</ref> '''1876 August 10''', Louisa Augusta Beatrice Montagu (daughter) and Archibald Acheson married. '''1889 January 5''', Alice Maude Olivia Montagu (daughter) and Edward Stanley married. '''1890 March 22''', William Drogo Montagu (7th Duke) died.<ref name=":3">"William Drogo Montagu, 7th Duke of Manchester." {{Cite web|url=http://www.thepeerage.com/p10128.htm#i101274|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1890 November 14''', William Angus Drogo Montagu (grandson) and Helena Zimmerman married secretly, in London.<ref>"Helena Zimmerman." {{Cite web|url=http://www.thepeerage.com/p34555.htm#i345545|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1892 August 16''', Louise Friederike Auguste Gräfin von Alten Montagu and Spencer Compton Cavendish, her second husband, married.<ref name=":2" /> '''1897 July 2, Friday''', Louise Cavendish (#18 on the list of attendees) hosted her famous [[Social Victorians/1897 Fancy Dress Ball| fancy-dress ball]] at Devonshire House in London. '''1897 July 20''', Mary Louise Elizabeth Montagu Douglas-Hamilton and Robert Carnaby Foster married. '''1900 November 14''', William Angus Drogo Montagu and Helena Zimmerman married.<ref>{{Cite journal|date=2020-07-17|title=Helena, Countess of Kintore|url=https://en.wikipedia.org/w/index.php?title=Helena,_Countess_of_Kintore&oldid=968067371|journal=Wikipedia|language=en}}</ref> '''1901 Spring''', Paris, Consuelo Spencer-Churchill, Duchess of Marlborough, describes a meeting with Louise Cavendish in the spring following Queen Victoria's death at the horse racetrack, Longchamps:<blockquote>A renowned character and virtually dictator of what was known as the fast set as opposed to the Victorian, Her Grace was a German aristocrat by birth. She had first been married to the impoverished Duke of Manchester, and when he died had improved her status by marriage to the rich Duke of Devonshire, who waged an undisputed influence in politics. Rumour had her beautiful, but when I knew her she was a raddled old woman, covering her wrinkles with paint and her pate with a brown wig. Her mouth was a red gash and from it, when she saw me, issued a stream of abuse. How could I, she complained, pointing to my white gloves, show so little respect to the memory of a great Queen? What a carefree world we must have lived in, that etiquette even in such small matters could assume so much importance?<ref>Balsan, Consuelo Vanderbilt. ''The Glitter and the Gold: The American Duchess — In Her Own Words''. New York: St. Martin's, 1953.</ref>{{rp|p. 115}}</blockquote> === Annual Events === Every year, as Duchess of Devonshire, Louise held a dance on the night after the Derby at Epsom Downs, which at this point was held on Wednesdays after Easter. == Costume at the Duchess of Devonshire's 2 July 1897 Fancy-dress Ball == [[File:Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra.jpg|thumb|Louise, Duchess of Devonshire as Zenobia, Queen of Palmyra|alt=Louise, Duchess of Devonshire in costume as Zenobia, Queen of Palmyra]] At their fancy-dress ball, Louisa, Duchess of Devonshire sat at Table 1 during the first seating for supper, escorted in to the table by the Prince of Wales.<ref name=":7">"Fancy Dress Ball at Devonshire House." ''Morning Post'' Saturday 3 July 1897: 7 [of 12], Col. 4a–8 Col. 2b. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970703/054/0007.</ref>{{rp|p. 7, Col. 4c}} Her costume was designed by M. Comelli (Attillo Giuseppe Comelli, 1858–1925, artist and costumier for opera, ballet and theatre in London as well as Europe and the U.S.<ref>{{Cite book|url=https://books.google.com/books?id=SZh2DwAAQBAJ&pg=PT207&lpg=PT207&dq=Attilio+Comelli&source=bl&ots=lFB0If7CwV&sig=ACfU3U1_Ost_lhmMvzMMs6NvuhK5SlRhJw&hl=en&sa=X&ved=2ahUKEwjKlsTw2sH3AhXYAp0JHVIxDWA4KBDoAXoECBAQAw#v=onepage&q=Attilio%20Comelli&f=false|title=Forgotten Designers Costume Designers of American Broadway Revues and Musicals From 1900-1930|last=Unruh|first=Delbert|date=2018-11-06|publisher=Page Publishing Inc|isbn=978-1-64082-758-5|language=en}} N.P.</ref>)<ref name=":5">“The Devonshire House Ball.” The ''Man of Ross'' 10 July 1897, Saturday: 2 [of 8], Col. 4b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0001463/18970710/033/0002.</ref> <ref name=":8">"The Duchess of Devonshire's Fancy Dress Ball. Special Telegram." ''Belfast News-Letter'' Saturday 03 July 1897: 5 [of 8], Col. 9 [of 9]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/BL/0000038/18970703/015/0005.</ref>{{rp|p. 5, Col. 9a}} <ref name=":9">"By One Who Was There." “The Duchess’s Costume Ball.” ''Westminster Gazette'' 03 July 1897 Saturday: 5 [of 8], Cols. 1a–3b [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0002947/18970703/035/0005.</ref> and constructed by the House of Worth. According to Russell Harris,<blockquote>For her costume, the Duchess commissioned Monsieur Comelli (1858-1925), a well-known designer of opera costumes for the London theatre and opera stage, and then had the design made up by Worth of Paris. ''Munsey’s Magazine'' noted “it is safe to say that the Queen of Palmyra never owned such a sumptuous costume in her lifetime.”<ref>Harris, Russell. {{Cite web|url=http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html|title=Louise, Duchess of Devonshire, née Countess von Alten of Hanover (1832-1911), as Zenobia, Queen of Palmyra|website=www.rvondeh.dircon.co.uk|access-date=2022-05-05}} ''Narrated in Calm Prose: Photographs from the V&A's Lafayette Archive of Guests in Costume at the Duchess of Devonshire's Diamond Jubilee Ball, July 1897''. http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html.</ref></blockquote>Lafayette's portrait of "Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester)" in costume is photogravure #5 in the album presented to the Duchess of Devonshire and now in the National Portrait Gallery.<ref>"Devonshire House Fancy Dress Ball (1897): photogravures by Walker & Boutall after various photographers." 1899. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait-list.php?set=515.</ref> The printing on the portrait says, "The Duchess of Devonshire as Zenobia Queen of Palmyra," with a Long S in ''Duchess''.<ref>"Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra." Devonshire House Fancy Dress Ball Album. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait/mw158357/Louise-Frederica-Augusta-Cavendish-ne-von-Alten-Duchess-of-Devonshire-formerly-Duchess-of-Manchester-as-Zenobia-Queen-of-Palmyra.</ref> Often, the V&A Lafayette Archive contains more than one portrait of a sitter for this ball, but the uncropped portrait (above right), which shows the unfinished end of the balustrade in front of the Duchess and the edge of the painted flat behind it, seems to have been the only portrait taken by Lafayette of the Duchess in costume. The copy owned by the National Portrait Gallery in London and the copy included in the album are cropped so that those unfinished edges do not show, but they appear to be from the same photograph. '''[Stuff about entourage below in case you're interested.]''' === The Duchess and Her Entourage === Louise, Duchess of Devonshire was dressed as Zenobia, Queen of Palmyra. Besides the Duke of Devonshire, her retinue included her grandson, [[Social Victorians/People/William Angus Drogo Montagu|William Angus Drago Montagu, 9th Duke of Manchester]], dressed as a Georgian courtier. According to a single source, the Belfast ''News-Letter'', the rest of her entourage — all in costume — seems to have been made up of the following: * Four children * Four trumpeters * Four fan-bearers Three newspapers — The Belfast ''News-Letter'', the ''Man of Ross'' and the ''Westminster Gazette'' — say that the Duchess's entourage included three groups: children, trumpeters and fan-bearers. Only the Belfast ''News-Letter'' says that each group had four members. These three sources describe the Duchess's retinue and how the people in it were dressed: *"The Duchess of Devonshire was dazzingly [sic] magnificent as 'Zenobia,' arrayed in the glistening fabrics and massive jewels in which artists have delighted to depict the Warrior Queen, the costume in this case being specially designed by the clever French artist, M. Comelli, who was also responsible for the splendid attire of the Queen's suite. This was composed of four children in white Assyrian robes, draped with pink shawls; four trumpeters in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel; and four fan-bearers attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold — a gloriously magnificent pageant."<ref name=":8" />{{rp|p. 5, Col. 9a}} *"The duchess was dressed as Zenobia, in gold cloth, gorgeously embroidered in gold, brilliants, and coloured stones, and opening over an under dress of white crêpe de Chine, worked finely in brilliants. The train of light green velvet was lined with blue, and sumptuously embroidered in jewels and gold, the colouring being particularly artistic. With this dress were worn splendid jewels, and a large horn crown, encrusted with diamonds, emeralds, and rubies. The duchess was attended by a suite of children, trumpeters, and fan-bearers, all picturesquely attired in Assyian [sic] costumes — the whole group being specially designed by M. Comelli."<ref name=":5" /> *"The host was dressed as Charles V. of Germany, in black velvet, satin, and fur; and the Duchess made the most gorgeous of Zenobias, in a gown of gold gauze, and a green velvet train — both a mass of exquisite oriental embroidery. The crown and hanging ropes of pearls, the jewelled girdle, and the train of children, fan-bearers, and trumpeters — all in Babylonish garb — as designed by M. Comelli, made a gloriously imposing and picturesque group."<ref name=":9" /> ==== Details of the Costumes in the Entourage ==== The Archives of the Duke of Devonshire (Devonshire Collections, Chatsworth) has "receipts" or invoices that functioned as receipts for several commercial concerns that were involved in making costumes or accessories for costumes for this ball. They are the following: * B. Burnet & Co. * Arthur Millward, Theatrical Jeweller * M. (Attillo Giuseppe) Comelli * Liberty & Co. * Lafayette, Ltd. * Goldsmith, Pearl & Diamond Merchant, & Silversmith This list of commercial concerns almost certainly cannot be the complete list of all concerns that contributed to the costumes. These are the only receipts or invoices about expenses for the ball, however, that the Chatsworth Archive contains; similar documents were likely not even kept or were destroyed with other papers not considered worth retaining for the archive. The Chatsworth Archive calls these documents receipts, which indeed they are because they were returned to the Duchess's private secretary, in fact, as receipts. From our perspective, though, they are invoices that contain specifics about what was used to make the costumes. The analysis of these invoices has led us to an understanding of what the people who attended the Duchess in her entourage wore and even how many people were in that entourage. To develop this understanding, it has been necessary to analyze the items listed on the invoices and their pricing, some of which is included below, in the section for each invoice. '''[blather begins here]''' It is difficult to make sense of some of the detail on the invoices we have. For example, elements of the costumes in the invoice usually suggests two costumes for each group, but it is not always clear which or how many costumes are being described. If each group contained four members (as the Belfast ''News-Letter'' says), then other suppliers must have made some of these costumes or other invoices and receipts from these businesses existed at that time. Based on the receipts More likely, perhaps, is that the Belfast ''News-Letter'' is wrong about the number of people in each group, which perhaps contained only two rather than four members. The business concerns listed above were specialized and likely used for different elements of the costumes. As a theatrical designer, Comelli would have depended on the suppliers he knew and arranged with them for the construction of these costumes. [tights, etc., here??] ===== B. Burnet & Co. ===== An invoice and receipt from B. Burnet & Co., held in the Archives of the Duke of Devonshire, has specific information about some of the fabrics, trims and accessories purchased for the costumes of the Duchess's retinue.<ref name=":11">B. Burnet & Co. to Louise, Duchess of Devonshire. Date of invoice 2 and 6 July 1897; postmarked 25 October 1897, for receipt of payment(?). The Devonshire Collections, Chatsworth, Reference number L/109/4(3).</ref> Besides itemizing some costume or accessory elements that seem to be for each group, the invoice also lists items not easy to associate with particular costumes, like the following: * 12 yards of White silk fringe 8in deep<ref name=":11" />{{rp|back left}} * 12 1/2 yards of "wht cloth"<ref name=":11" />{{rp|back left}} * 9 yards of "Selesia"<ref name=":11" />{{rp|back left}} * 2 yards of Canvas<ref name=":11" />{{rp|back right}} * 4 Tan Wool Tights<ref name=":11" />{{rp|back right}} * 2 Tan Boys Tights<ref name=":11" />{{rp|back right}} At this time, we are not sure which costumes these elements were used for. Possibly the white silk fringe and the white cloth would have been used to construct the robes for the children and trumpeters in the entourage. The number of tights suggests that the six costumes on this invoice all included tights. With other elements of the trumpeters' costumes, the Burnet invoice also lists "6 prs Assyrian Buskins." Probably, to a late Victorian, buskins would have been "defensive leggings"<ref>Demmin, Auguste. An illustrated History of Arms and Armour: From the Earliest Period to the Present Time. George Bell, 1894. Google Books https://books.google.com/books?id=ArRCAAAAYAAJ: 106.</ref> laced together and covering the lower leg and often feet of a soldier. To a clothing and military historian, buskins (or greaves) were worn by people in a number of cultures over millennia and varied widely in style and construction. Buskins appear in Assyrian art held at the time by the British Museum. Listing six pairs of buskins suggests that every costume in the Duchess's entrourage included buskins, possibly worn over the tan tights. Besides helmets and cuirasses, the trumpeters may also have worn The Burnet invoice lists "4 Broad Belts," which may have held "4 Skins Fleshers."<ref name=":11" />(p. 1, front of invoice) (A skin flesher is a kind of knife used to separate the skin from the meat in animals.) If each group included only two members, then perhaps the belts and fleshers were worn not only by the trumpeters but also by the fan-bearers. The Millward invoice lists "8 Doz 'Plaques' for Belts'" with a drawing of an upright rectangle with a circle in the middle, which might have been a jewel. Double lines around the rectangle suggest that the plaques were not flat or the metal was not thin. The drawing does not give any ideas about how the plaques were attached to the belts, if they were. A different hand, probably "[L.??] L. Collier," wrote the following sentence at the end of the invoice and receipt, above the postmark:<blockquote>All the above named articles were used for the six [?] dresses made for the Devonshire Ball.<ref name=":11" />(back right)</blockquote>This same hand, signing what is possibly "Floyd Collier," also signed the postmark of the Comelli invoice and receipt. On the Burnet document, this writer, possibly an assistant or employee of the Duchess of Devonshire, says that "six dresses" were made (if in fact, that word is ''six''). (No "Collier" is listed among the staff or servants of the Duke of Devonshire at the end of the 19th century.<ref>"Servants A-H." ''Historic Servants and Staff. Servants and Staff Database''. Retrieved 18 July 2022 https://www.chatsworth.org/media/11528/servants-a-h.pdf.</ref> The invoice appears to itemize materials used for six costumes: two children, two trumpeters and two fan-bearers. ===== Arthur Millward, Theatrical Jeweller ===== An invoice and request for payment from Arthur Millward, Theatrical Jeweller, held in the Archives of Chatsworth House, has more specifics about some of the fabrics, trims and accessories for the costumes of the Duchess's retinue.<ref name=":12">Memorandum. Arthur Millward, Theatrical Jeweller, to Louise, Duchess of Devonshire. Date of itemized invoice 1 July 1897; date of request for payment(?) 27 August 1897. The Devonshire Collections, Chatsworth, Reference number L/109/4(?).</ref> This invoice lists the following, which could have been used in any of the costumes for the entourage: * 8 Doz 'Plaques' for Belts * 4 Large Armlets * 4 Bracelets * 8 Armlets<ref name=":12" />(2, back) Because Millward was a Theatrical Jeweller, it seems likely that most (if not all) of the items listed on the invoice were made of metal and the jewels mentioned were artificial, made of glass or paste. Other items on the invoice seem to belong to the costumes of the trumpeters, which the Belfast ''News-Letter'' says included helmets: * 2 Helmets * 2 Centre pieces The Millward invoice shows tiny line drawings next to the words ''2 Helmets'' and ''2 Centre pieces''. These drawings suggest that the Centre pieces were attached to the helmets rather than being anything that would have been put on a table as decoration. Other items seem to belong to the costumes of the fan-bearers: * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers The "Pearl & Gold Headdresses" were likely the "jewelled diadems" mentioned in the Belfast ''News-Letter''. The "Fan properties with Feathers" are likely to have been the "long-handled fans of white feathers, mounted in blue and gold" mentioned in the newspaper report.<ref name=":8" />(p. 5, Col. 9a) At the end of the Millward invoice, a "reduction as agreed with M [Mr?] Commelli [sic]" of £1 10''s'' is subtracted from a total of £22 3''s''. No reason for this reduction is given.<ref name=":12" />(2, back) ===== Details for the Children in the Entourage ===== According to the ''Belfast News-Letter'', four children were "in white Assyrian robes, draped with pink shawls."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for "White Cloth Dresses":<ref name=":11" />{{rp|p. 2, back left of invoice}} * "2 Terra Gown draperies with Stars 200 in all" * "2 Cloth fronts embroidered with Square Medallions down centre" * "2 do do [ditto ditto, that is, cloth fronts] embroidered double border down front each side and collar" * "4 Sleeves embroidered Small Medallions" The Burnet & Co. invoice lists 6 yards of "Terra" Silk Fringe, which perhaps was used to trim the "terra draperies," or shawls, made from 3 1/4 yards of "Light Terra Satinette" worn by the children? ===== Details for the Trumpeters in the Entourage ===== According to the ''Belfast News-Letter'', four trumpeters were "in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel."<ref name=":8" />{{rp|p. 5, Col. 9a}} The trumpeters appear to have been dressed as soldiers or military men. According to the B. Burnet invoice, the following was purchased for the trumpeters' costumes:<ref name=":11" />{{rp|p. 1, front of invoice}} * 7 '''units (yards?)''' of purple silk [probably used for shawls] * "2 skirt fronts with border alround [sic]" * "2 sets of Leather Cuarasses [sic] Embroidered front & back" * "4 Sleeves embroidered loop stitch" The Millward invoice lists * 2 Helmets * 2 Centre Pieces [probably for helmets rather than table decorations] ===== Details for the Fan-bearers in the Entourage ===== According to the ''Belfast News-Letter'', four fan-bearers were "attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for the fan bearers's costumes:<ref name=":11" />{{rp|pp. 1–2, front and left-back of invoice}} * "Embroidering 2 Crimson draperies with Stars 334 in all" * "2 Top [?] fronts embroidered & round necks" * "4 Sleeves embroidered long stitch"The Millward invoice lists * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers<ref name=":12" />(2, back) The Burnet & Co. invoice lists 12 yards of "Red Silk Fringe," which perhaps was used to trim the "crimson shawls" or "Crimson draperies," which may have been made from the 5 yards of "Red Satinette." Again, this list suggests two rather than four costumes. === Newspaper Descriptions of the Duchess's Costume === These almost exactly identical descriptions suggest [[Social Victorians/1897 Fancy Dress Ball/anthology#Scissors-and-Paste Journalism|scissors-and-paste journalism]] or a shared primary source: * "The Duchess of Devonshire was a dazzling vision, dressed as 'Zenobia,' in a glistening gold gauze gown, elaborately ornamented with suns and discs, wrought in purple and green gems outlined with gold, and having a large diamond as centre. The space between was fluted with fine silver spangles. This robe was open in front over an under dress of white crépe de chine, delicately worked in crystals, and at each side of the opening on the gold robe were large fan-shaped groups of peacock feathers, worked in multicoloured jewels. '''The corsage''' was to correspond, and had a magnificent girdle of jewels, the train of bright green velvet, hung like a fan, without folds, being fastened at each side of the shoulders by diamond brooches, and caught at the waist with a similar ornament. It was a mass of gorgeous embroidery, carried out in heliotrope velvet, lotus flowers studded with tinted gems, and other devices in terra-cotta and electric blue velvet — all enriched with gold, diamond, and jewelled embroidery — and lined with pale blue satin. The crown worn with this was high, and of filigree gold, surmounted with two horns, each tipped with a large diamond. It was encrusted with large diamonds, rubies, and emeralds, and long chains of pearls fell under the chin and about the head — one magnificent pear-shaped pearl resting on the forehead. Attending the hostess were four children, four fan-bearers, and four trumpeters, all magnificently arrayed in artistically embroidered Assyrian robes, helmets, and other accessories, correct in every detail."<ref>"Duchess of Devonshire's Fancy Ball. A Brilliant Spectacle. Some of the Dresses." London ''Daily News'' Saturday 3 July 1897: 5 [of 10], Col. 6a–6, Col. 1b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000051/18970703/024/0005 and http://www.britishnewspaperarchive.co.uk/viewer/BL/0000051/18970703/024/0006.</ref>{{rp|p. 5, Col. 6a}} * "The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume, supplied by Worth, of Paris. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels, outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jewelled belt. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end, and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls, with a large pear-shaped pearl in the centre falling on the forehead."<ref>“The Ball at Devonshire House. Magnificent Spectacle. Description of the Dresses.” London ''Evening Standard'' 3 July 1897 Saturday: 3 [of 12], Cols. 1a–5b [of 7]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000183/18970703/015/0004.</ref>{{rp|p. 3, Col. 2b}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crepe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crepe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jeweled belt. A gold crown encrusted with emeralds, diamonds, and rubies with a diamond drop at each curved end and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":7" />{{rp|p. 7, Col. 7a}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks’ outspread tails. This opened to show an underdress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls and sprinkled all over with diamonds. The train, which was attached to the shoulders by two slender points and was fastened at the waist with a large diamond ornament, was a green velvet of a lovely shade, and was superbly embroidered in Oriental designs introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, with four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine hidden with a stomacher of real diamonds, rubies and emeralds. Jewelled belt. A gold crown incrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":6">"Ball at Devonshire House." The ''Times'' Saturday 3 July 1897: 12, Cols. 1A–4C ''The Times Digital Archive''. Web. 28 Nov. 2015.</ref>{{rp|p. 12, Col. 3b}} *According to the article in ''The Graphic'', written by [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] though this caption to the Lafayette photograph seems to have been boilerplate and printed in other places, the Duchess of Devonshire wore a "Skirt of gold tissue, embroidered all over with emeralds, sapphires, diamonds, and other jewels outlined with gold. This opened to show an underdress of crème crêpe de chine, embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was green velvet, superbly embroidered in Oriental designs. The bodice was composed of gold tissue, and the front was of crêpe de chine hidden with a stomacher of diamonds, rubies, and emeralds. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre."<ref name=":10">Greville, Violet, Lady. "Devonshire House Ball." The ''Graphic'' Saturday 10 July 1897: 15 [of 24]: Col. 1a–16, Col. 1c. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000057/18970710/019/0015.</ref>{{rp|p. 15, Col. 3b}} *The ''Guernsey Star'' describes first [[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish, Duke of Devonshire]] and then Louisa, Duchess: "The host himself personated Charles V. of Germany in a costume copied from a celebrated picture by Titian, while the hostess was attired with great Oriental magnificence as Zenobia. Her dress was tissue of silver in front [sic], wrought with jewels. The over-dress was cloth of gold magnificently wrought with jewels, and Her Grace wore a bandeau of gold round her head, studded with diamonds, turquoise, and emeralds, and surrounded by hanging chains of superb pearls."<ref>"Duchess of Devonshire's Fancy-Dress Ball. Brilliant Spectacle." The [Guernsey] ''Star'' 6 July 1897, Tuesday: 1 [of 4], Col. 1a–2b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000184/18970706/003/0001.</ref>{{rp|p. 1, Col. 2a}} Gossipy newspaper reports before the ball reported on how costumes were being made. For example, according to the Edinburgh ''Evening News'' on 21 June 1897, less than two weeks before the party, "The ball being a fancy dress one, men as well as women will be able in certain characters to wear jewels. The Duchess of Devonshire, who is to appear as Zenobia, is getting her jewels reset after the antique style."<ref>“The Duchess of Devonshire’s Ball.” Edinburgh ''Evening News'' 21 June 1897, Monday: 4 [of 6], Col. 5c [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000452/18970621/079/0004.</ref> While almost all descriptions of her mention her jewels because they were sewn onto the costume itself, these emphasize her jewelry: * "The Duchess was attired with great Oriental magnificence as Zenobia. Her dress was a tissue of silver, embroidered with gold and jewels, an overmantle of cloth of gold embroidered in the same manner hung from the shoulders, and she wore a bandeau of gold studded with gems, and surrounded by hanging chains of pearls over her elaborate headdress; strings and ropes of jewels and pearls were worn round the neck, and hung down almost to the knees."<ref>“The Duchess of Devonshire’s Ball.” The ''Gentlewoman'' 10 July 1897 Saturday: 32–42 [of 76], Cols. 1a–3c [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0003340/18970710/155/0032. </ref>{{rp|p. 32, Cols. 1c–2a}} * "A wonderfully beautiful dress was that which was worn by the Duchess of Devonshire as Zenobia, Queen of Palmyra. It was of golden tissue, sewn with silver paillettes, and jewelled with diamonds and other precious stones. In front there were silk embroideries, in many vivid shades of colour, and here the golden draperies opened to show a petticoat of white crêpe de chine, embroidered with pearls and gold. The short train was of brilliant green velvet, exquisitely embroidered. One of the Duchess of Devonshire’s beautiful diamond and emerald tiaras had been taken to pieces to form a stomacher, the effect of which was dazzling in its brilliancy. Long chains of pearls and other wonderful jewels were worn with this beautiful dress."<ref>“The Devonshire House Ball. A Brilliant Gathering.” The ''Pall Mall Gazette'' 3 July 1897, Saturday: 7 [of 10], Col. 2a–3a [of 3]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000098/18970703/019/0007.</ref>{{rp|p. 7, Col. 2b}} * In the article about the ball in the ''Graphic'', [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] says, "The Ducal hostess herself elected to appear as Zenobia, Queen of Palmyra, with lavish magnificence, and wearing a corruscation of jewels which must have eclipsed the state of even the all-subduing majesty the Duchess impersonated."<ref name=":10" />{{rp|p. 16, Col. 1a}} *The Duchess was dressed "as Zenobia, Queen of Palmyra, her dress a marvel of soft tissues and exquisite ornament, and her tiara a still greater marvel of the jeweller's art."<ref name=":6" />{{rp|p. 12, Col. 2a}} <ref>"The Duchess of Devonshire’s Historic Ball. Some of the Fancy Costumes." Supplement. The ''Leicester Chronicle and Leicestershire Mercury'' 10 July 1897, Saturday: 11 [of 12], Cols. 4a–b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000173/18970710/141/0011.</ref>{{rp|p. 11, 4a}} === The Historical Zenobia === Zenobia (240 – c. 274) was queen of the Syrian Palmyrene Empire, ruling as regent for her son after her husband's assassination.<ref>{{Cite journal|date=2022-05-03|title=Zenobia|url=https://en.wikipedia.org/w/index.php?title=Zenobia&oldid=1086005949|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Zenobia.</ref> She was the subject of much art in the 19th century, including literature, opera, sculpture, and paintings. Middle-eastern traveller Lady Hester Stanhope (1776–1839) discussed Zenobia in her memoirs, published in 1847.<ref>{{Cite journal|date=2022-03-07|title=Lady Hester Stanhope|url=https://en.wikipedia.org/w/index.php?title=Lady_Hester_Stanhope&oldid=1075838273|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Lady_Hester_Stanhope.</ref> == Demographics == *Nationality: born in Hanover, in what is now Germany<ref name=":0">{{Cite journal|date=2020-07-27|title=Louisa Cavendish, Duchess of Devonshire|url=https://en.wikipedia.org/w/index.php?title=Louisa_Cavendish,_Duchess_of_Devonshire&oldid=969824214|journal=Wikipedia|language=en}}</ref> === Residences === ==== As Duchess of Manchester ==== *Kimbolton Castle, Huntingdonshire *Manchester House, London ==== As Duchess of Devonshire ==== *Devonshire House, London (mid-April until mid-July, for the Season) *Compton Place, Eastbourne (mid-July until 12 August<ref name=":1" />{{rp|p. 32}}) *Bolton Abbey, Yorkshire (12 August until the middle of September<ref name=":1" />{{rp|p. 32}}) *Chatsworth, Derbyshire (middle of September until early Spring<ref name=":1" />{{rp|p. 32}}) *Lismore Castle, County Waterford (early Spring until the middle of April<ref name=":1" />{{rp|p. 32}}) == Family == *Louisa (or Luise) Friederike Auguste Gräfin von Alten Montagu Cavendish (15 January 1832 – 15 November 1911)<ref name=":2" /><ref name=":0" /> *William Drogo Montagu, 7th Duke of Manchester (15 October 1823 – 22 March 1890)<ref name=":3" /><ref>{{Cite journal|date=2020-09-07|title=William Montagu, 7th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=William_Montagu,_7th_Duke_of_Manchester&oldid=977197445|journal=Wikipedia|language=en}}</ref> #George Victor Drogo Montagu, 8th Duke of Manchester (17 June 1853 – 18 August 1892) #Mary Louise [Louisa?] Elizabeth Montagu Douglas-Hamilton Forster (27 December 1854 – 10 February 1934) #Louisa Augusta Beatrice Montagu Acheson (c. 1856 – 3 March 1944) #Charles William Augustus Montagu (23 November 1860 – 10 November 1939) #Alice Maude Olivia Montagu Stanley (15 August 1862 – 23 July 1957) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], 8th Duke of Devonshire (23 July 1833 – 24 March 1908) == Notes and Questions == #As Duchess of Manchester Luise was not invited to the wedding between Bertie and Alix, Victoria's punishment for Luise's having gotten the Duke of Derby to promise her the position of Mistress of the Robes (and then exacting that promise).<ref>Leslie, Anita. ''The Marlborough House Set''. New York: Doubleday, 1973.</ref>{{rp|pp. 47–48}} #"As a young woman she was extremely beautiful; Princess Catherine Radziwill saw her at a reception given by the Empress of Germany and recalls on being introduced to her 'how she struck me as the loveliest creature I had ever set eyes upon. Indeed I have only met three women in my whole existence who could be compared to her.'"<ref name=":1" />{{rp|p. 21}} == Footnotes == {{reflist}} 8qf0y9b7yiy0ddojln6rmtexp91lqvy 2408231 2408184 2022-07-20T22:46:15Z Scogdill 1331941 wikitext text/x-wiki == Also Known As == *Louise, Duchess of Devonshire *Louisa, Duchess of Manchester *Luise Friederike August Gräfin von Alten *Louisa Montagu *Louise Cavendish *The Double Duchess == Acquaintances, Friends and Enemies == === Friends === *[[Social Victorians/People/Albert Edward, Prince of Wales | Albert Edward, Prince of Wales]] (beginning about 1852) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], Lord Hartington (later 8th Duke of Devonshire) *Daisy, Lady Warwick *Lady Mayoress, Mrs. Benjamin Samuel Faudel-Phillips, 2nd Baronet,<ref>{{Cite journal|date=2020-08-25|title=Faudel-Phillips baronets|url=https://en.wikipedia.org/w/index.php?title=Faudel-Phillips_baronets&oldid=974879290|journal=Wikipedia|language=en}}</ref> presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4">"The Queen's Drawing Room" ''Morning Post'' 25 February 1897 Thursday: 5 [of 10], Col. 5a–7b [of 8]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970225/047/0005.</ref>{{rp|p. 5, Col. 6c}} *Mrs. J. E. Mellor, presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4" />{{rp|p. 5, Col. 6c}} === Enemies === * Consuelo, Duchess of Marlborough (at least, in 1901)<ref name=":1">Murphy, Sophia. ''The Duchess of Devonshire's Ball''. London: Sidgwick & Jackson, 1984.</ref>{{rp|pp. 31–32}} == Organizations == == Timeline == '''1852 July 22''', Luise Friederike Auguste Gräfin von Alten and William Drogo Montagu married.<ref name=":2">"Luise Friederike Auguste Gräfin von Alten." {{Cite web|url=http://www.thepeerage.com/p10947.htm#i109469|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1863, early, or late 1862''', Louise and Spencer Compton Cavendish began a relationship.<ref name=":1" />{{rp|p. 26}} '''1873 December 10''', Mary Louise Elizabeth Montagu (daughter) and William Douglas-Hamilton married. '''1876 May 22''', Consuelo Iznaga y Clement and George Victor Drogo Montagu (son) married in Grace Church, New York City.<ref>{{Cite journal|date=2020-08-24|title=George Montagu, 8th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=George_Montagu,_8th_Duke_of_Manchester&oldid=974659520|journal=Wikipedia|language=en}}</ref><ref>{{Cite journal|date=2020-07-27|title=Consuelo Montagu, Duchess of Manchester|url=https://en.wikipedia.org/w/index.php?title=Consuelo_Montagu,_Duchess_of_Manchester&oldid=969888488|journal=Wikipedia|language=en}}</ref> '''1876 August 10''', Louisa Augusta Beatrice Montagu (daughter) and Archibald Acheson married. '''1889 January 5''', Alice Maude Olivia Montagu (daughter) and Edward Stanley married. '''1890 March 22''', William Drogo Montagu (7th Duke) died.<ref name=":3">"William Drogo Montagu, 7th Duke of Manchester." {{Cite web|url=http://www.thepeerage.com/p10128.htm#i101274|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1890 November 14''', William Angus Drogo Montagu (grandson) and Helena Zimmerman married secretly, in London.<ref>"Helena Zimmerman." {{Cite web|url=http://www.thepeerage.com/p34555.htm#i345545|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1892 August 16''', Louise Friederike Auguste Gräfin von Alten Montagu and Spencer Compton Cavendish, her second husband, married.<ref name=":2" /> '''1897 July 2, Friday''', Louise Cavendish (#18 on the list of attendees) hosted her famous [[Social Victorians/1897 Fancy Dress Ball| fancy-dress ball]] at Devonshire House in London. '''1897 July 20''', Mary Louise Elizabeth Montagu Douglas-Hamilton and Robert Carnaby Foster married. '''1900 November 14''', William Angus Drogo Montagu and Helena Zimmerman married.<ref>{{Cite journal|date=2020-07-17|title=Helena, Countess of Kintore|url=https://en.wikipedia.org/w/index.php?title=Helena,_Countess_of_Kintore&oldid=968067371|journal=Wikipedia|language=en}}</ref> '''1901 Spring''', Paris, Consuelo Spencer-Churchill, Duchess of Marlborough, describes a meeting with Louise Cavendish in the spring following Queen Victoria's death at the horse racetrack, Longchamps:<blockquote>A renowned character and virtually dictator of what was known as the fast set as opposed to the Victorian, Her Grace was a German aristocrat by birth. She had first been married to the impoverished Duke of Manchester, and when he died had improved her status by marriage to the rich Duke of Devonshire, who waged an undisputed influence in politics. Rumour had her beautiful, but when I knew her she was a raddled old woman, covering her wrinkles with paint and her pate with a brown wig. Her mouth was a red gash and from it, when she saw me, issued a stream of abuse. How could I, she complained, pointing to my white gloves, show so little respect to the memory of a great Queen? What a carefree world we must have lived in, that etiquette even in such small matters could assume so much importance?<ref>Balsan, Consuelo Vanderbilt. ''The Glitter and the Gold: The American Duchess — In Her Own Words''. New York: St. Martin's, 1953.</ref>{{rp|p. 115}}</blockquote> === Annual Events === Every year, as Duchess of Devonshire, Louise held a dance on the night after the Derby at Epsom Downs, which at this point was held on Wednesdays after Easter. == Costume at the Duchess of Devonshire's 2 July 1897 Fancy-dress Ball == [[File:Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra.jpg|thumb|Louise, Duchess of Devonshire as Zenobia, Queen of Palmyra|alt=Louise, Duchess of Devonshire in costume as Zenobia, Queen of Palmyra]] At their fancy-dress ball, Louisa, Duchess of Devonshire sat at Table 1 during the first seating for supper, escorted in to the table by the Prince of Wales.<ref name=":7">"Fancy Dress Ball at Devonshire House." ''Morning Post'' Saturday 3 July 1897: 7 [of 12], Col. 4a–8 Col. 2b. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970703/054/0007.</ref>{{rp|p. 7, Col. 4c}} Her costume was designed by M. Comelli (Attillo Giuseppe Comelli, 1858–1925, artist and costumier for opera, ballet and theatre in London as well as Europe and the U.S.<ref>{{Cite book|url=https://books.google.com/books?id=SZh2DwAAQBAJ&pg=PT207&lpg=PT207&dq=Attilio+Comelli&source=bl&ots=lFB0If7CwV&sig=ACfU3U1_Ost_lhmMvzMMs6NvuhK5SlRhJw&hl=en&sa=X&ved=2ahUKEwjKlsTw2sH3AhXYAp0JHVIxDWA4KBDoAXoECBAQAw#v=onepage&q=Attilio%20Comelli&f=false|title=Forgotten Designers Costume Designers of American Broadway Revues and Musicals From 1900-1930|last=Unruh|first=Delbert|date=2018-11-06|publisher=Page Publishing Inc|isbn=978-1-64082-758-5|language=en}} N.P.</ref>)<ref name=":5">“The Devonshire House Ball.” The ''Man of Ross'' 10 July 1897, Saturday: 2 [of 8], Col. 4b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0001463/18970710/033/0002.</ref> <ref name=":8">"The Duchess of Devonshire's Fancy Dress Ball. Special Telegram." ''Belfast News-Letter'' Saturday 03 July 1897: 5 [of 8], Col. 9 [of 9]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/BL/0000038/18970703/015/0005.</ref>{{rp|p. 5, Col. 9a}} <ref name=":9">"By One Who Was There." “The Duchess’s Costume Ball.” ''Westminster Gazette'' 03 July 1897 Saturday: 5 [of 8], Cols. 1a–3b [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0002947/18970703/035/0005.</ref> and constructed by the House of Worth. According to Russell Harris,<blockquote>For her costume, the Duchess commissioned Monsieur Comelli (1858-1925), a well-known designer of opera costumes for the London theatre and opera stage, and then had the design made up by Worth of Paris. ''Munsey’s Magazine'' noted “it is safe to say that the Queen of Palmyra never owned such a sumptuous costume in her lifetime.”<ref>Harris, Russell. {{Cite web|url=http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html|title=Louise, Duchess of Devonshire, née Countess von Alten of Hanover (1832-1911), as Zenobia, Queen of Palmyra|website=www.rvondeh.dircon.co.uk|access-date=2022-05-05}} ''Narrated in Calm Prose: Photographs from the V&A's Lafayette Archive of Guests in Costume at the Duchess of Devonshire's Diamond Jubilee Ball, July 1897''. http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html.</ref></blockquote>Lafayette's portrait of "Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester)" in costume is photogravure #5 in the album presented to the Duchess of Devonshire and now in the National Portrait Gallery.<ref>"Devonshire House Fancy Dress Ball (1897): photogravures by Walker & Boutall after various photographers." 1899. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait-list.php?set=515.</ref> The printing on the portrait says, "The Duchess of Devonshire as Zenobia Queen of Palmyra," with a Long S in ''Duchess''.<ref>"Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra." Devonshire House Fancy Dress Ball Album. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait/mw158357/Louise-Frederica-Augusta-Cavendish-ne-von-Alten-Duchess-of-Devonshire-formerly-Duchess-of-Manchester-as-Zenobia-Queen-of-Palmyra.</ref> Often, the V&A Lafayette Archive contains more than one portrait of a sitter for this ball, but the uncropped portrait (above right), which shows the unfinished end of the balustrade in front of the Duchess and the edge of the painted flat behind it, seems to have been the only portrait taken by Lafayette of the Duchess in costume. The copy owned by the National Portrait Gallery in London and the copy included in the album are cropped so that those unfinished edges do not show, but they appear to be from the same photograph. '''[Stuff about entourage below in case you're interested.]''' === The Duchess and Her Entourage === Louise, Duchess of Devonshire was dressed as Zenobia, Queen of Palmyra. Besides the Duke of Devonshire, her retinue included her grandson, [[Social Victorians/People/William Angus Drogo Montagu|William Angus Drago Montagu, 9th Duke of Manchester]], dressed as a Georgian courtier. According to a single source, the Belfast ''News-Letter'', the rest of her entourage — all in costume — seems to have been made up of the following: * Four children * Four trumpeters * Four fan-bearers Three newspapers — The Belfast ''News-Letter'', the ''Man of Ross'' and the ''Westminster Gazette'' — say that the Duchess's entourage included three groups: children, trumpeters and fan-bearers. Only the Belfast ''News-Letter'' says that each group had four members. These three sources describe the Duchess's retinue and how the people in it were dressed: *"The Duchess of Devonshire was dazzingly [sic] magnificent as 'Zenobia,' arrayed in the glistening fabrics and massive jewels in which artists have delighted to depict the Warrior Queen, the costume in this case being specially designed by the clever French artist, M. Comelli, who was also responsible for the splendid attire of the Queen's suite. This was composed of four children in white Assyrian robes, draped with pink shawls; four trumpeters in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel; and four fan-bearers attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold — a gloriously magnificent pageant."<ref name=":8" />{{rp|p. 5, Col. 9a}} *"The duchess was dressed as Zenobia, in gold cloth, gorgeously embroidered in gold, brilliants, and coloured stones, and opening over an under dress of white crêpe de Chine, worked finely in brilliants. The train of light green velvet was lined with blue, and sumptuously embroidered in jewels and gold, the colouring being particularly artistic. With this dress were worn splendid jewels, and a large horn crown, encrusted with diamonds, emeralds, and rubies. The duchess was attended by a suite of children, trumpeters, and fan-bearers, all picturesquely attired in Assyian [sic] costumes — the whole group being specially designed by M. Comelli."<ref name=":5" /> *"The host was dressed as Charles V. of Germany, in black velvet, satin, and fur; and the Duchess made the most gorgeous of Zenobias, in a gown of gold gauze, and a green velvet train — both a mass of exquisite oriental embroidery. The crown and hanging ropes of pearls, the jewelled girdle, and the train of children, fan-bearers, and trumpeters — all in Babylonish garb — as designed by M. Comelli, made a gloriously imposing and picturesque group."<ref name=":9" /> ==== Details of the Costumes in the Entourage ==== The Archives of the Duke of Devonshire (Devonshire Collections, Chatsworth) has "receipts" or invoices that functioned as receipts for several commercial concerns that were involved in making costumes or accessories for costumes for this ball. They are the following: * B. Burnet & Co. * Arthur Millward, Theatrical Jeweller * M. (Attillo Giuseppe) Comelli * Liberty & Co. * Lafayette, Ltd. * Goldsmith, Pearl & Diamond Merchant, & Silversmith This list of commercial concerns almost certainly cannot be the complete list of all concerns that contributed to the costumes. These are the only receipts or invoices about expenses for the ball, however, that the Chatsworth Archive contains; similar documents were likely not even kept or were destroyed with other papers not retained at some point in time. The business concerns listed above were specialized and likely used for different elements of the costumes. As a theatrical designer, Comelli would have depended on the suppliers he knew and arranged with them for the construction of these costumes. The Chatsworth Archive calls these documents ''receipts'', which indeed they are because they were returned to Devonshire House as receipts for payment. From our perspective, though, they are invoices that contain specifics about what was used to make the costumes. The analysis of these invoices has led to an understanding of what the people who attended the Duchess in her entourage wore and a clearer sense, perhaps, of how many people walked in that entourage. This analysis is based on the items listed on the invoices and their pricing, most of which is included in the section for each invoice, below. '''[blather begins here]''' It is not always clear in the invoices which or how many costumes are being described. If each group contained four members (as the Belfast ''News-Letter'' says<ref name=":8" />(p. 5, Col. 9a)), then other suppliers must have made some of these costumes or other invoices and receipts from these businesses must have existed at that time. The invoices, however, suggest that the Belfast ''News-Letter'' may have been wrong about the number of people in each group, which seem to have contained two rather than four members. [tights, etc., here??] ===== B. Burnet & Co. ===== An invoice and receipt from B. Burnet & Co., held in the Archives of the Duke of Devonshire, has specific information about some of the fabrics, trims and accessories purchased for the costumes of the Duchess's retinue.<ref name=":11">B. Burnet & Co. to Louise, Duchess of Devonshire. Date of invoice 2 and 6 July 1897; postmarked 25 October 1897, for receipt of payment(?). The Devonshire Collections, Chatsworth, Reference number L/109/4(3).</ref> Besides itemizing some costume or accessory elements that seem to be for each group, the invoice also lists items not easy to associate with particular costumes, like the following: * 12 yards of White silk fringe 8in deep<ref name=":11" />{{rp|back left}} * 12 1/2 yards of "wht cloth"<ref name=":11" />{{rp|back left}} * 9 yards of "Selesia"<ref name=":11" />{{rp|back left}} * 2 yards of Canvas<ref name=":11" />{{rp|back right}} * 4 Tan Wool Tights<ref name=":11" />{{rp|back right}} * 2 Tan Boys Tights<ref name=":11" />{{rp|back right}} At this time, we are not sure which costumes these elements were used for. Possibly the white silk fringe and the white cloth would have been used to construct the robes for the children and trumpeters in the entourage. The number of tights suggests that the six costumes on this invoice all included tights. With other elements of the trumpeters' costumes, the Burnet invoice also lists "6 prs Assyrian Buskins." Probably, to a late Victorian, buskins would have been "defensive leggings"<ref>Demmin, Auguste. An illustrated History of Arms and Armour: From the Earliest Period to the Present Time. George Bell, 1894. Google Books https://books.google.com/books?id=ArRCAAAAYAAJ: 106.</ref> laced together and covering the lower leg and often feet of a soldier. To a clothing and military historian, buskins (or greaves) were worn by people in a number of cultures over millennia and varied widely in style and construction. Buskins appear in Assyrian art held at the time by the British Museum. Listing six pairs of buskins suggests that every costume in the Duchess's entrourage included buskins, possibly worn over the tan tights. Besides helmets and cuirasses, the trumpeters may also have worn The Burnet invoice lists "4 Broad Belts," which may have held "4 Skins Fleshers."<ref name=":11" />(p. 1, front of invoice) (A skin flesher is a kind of knife used to separate the skin from the meat in animals.) If each group included only two members, then perhaps the belts and fleshers were worn not only by the trumpeters but also by the fan-bearers. The Millward invoice lists "8 Doz 'Plaques' for Belts'" with a drawing of an upright rectangle with a circle in the middle, which might have been a jewel. Double lines around the rectangle suggest that the plaques were not flat or the metal was not thin. The drawing does not give any ideas about how the plaques were attached to the belts, if they were. A different hand, probably "[L.??] L. Collier," wrote the following sentence at the end of the invoice and receipt, above the postmark:<blockquote>All the above named articles were used for the six [?] dresses made for the Devonshire Ball.<ref name=":11" />(back right)</blockquote>This same hand, signing what is possibly "Floyd Collier," also signed the postmark of the Comelli invoice and receipt. On the Burnet document, this writer, possibly an assistant or employee of the Duchess of Devonshire, says that "six dresses" were made (if in fact, that word is ''six''). (No "Collier" is listed among the staff or servants of the Duke of Devonshire at the end of the 19th century.<ref>"Servants A-H." ''Historic Servants and Staff. Servants and Staff Database''. Retrieved 18 July 2022 https://www.chatsworth.org/media/11528/servants-a-h.pdf.</ref> The invoice appears to itemize materials used for six costumes: two children, two trumpeters and two fan-bearers. ===== Arthur Millward, Theatrical Jeweller ===== An invoice and request for payment from Arthur Millward, Theatrical Jeweller, held in the Archives of Chatsworth House, has more specifics about some of the fabrics, trims and accessories for the costumes of the Duchess's retinue.<ref name=":12">Memorandum. Arthur Millward, Theatrical Jeweller, to Louise, Duchess of Devonshire. Date of itemized invoice 1 July 1897; date of request for payment(?) 27 August 1897. The Devonshire Collections, Chatsworth, Reference number L/109/4(?).</ref> This invoice lists the following, which could have been used in any of the costumes for the entourage: * 8 Doz 'Plaques' for Belts * 4 Large Armlets * 4 Bracelets * 8 Armlets<ref name=":12" />(2, back) Because Millward was a Theatrical Jeweller, it seems likely that most (if not all) of the items listed on the invoice were made of metal and the jewels mentioned were artificial, made of glass or paste. Other items on the invoice seem to belong to the costumes of the trumpeters, which the Belfast ''News-Letter'' says included helmets: * 2 Helmets * 2 Centre pieces The Millward invoice shows tiny line drawings next to the words ''2 Helmets'' and ''2 Centre pieces''. These drawings suggest that the Centre pieces were attached to the helmets rather than being anything that would have been put on a table as decoration. Other items seem to belong to the costumes of the fan-bearers: * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers The "Pearl & Gold Headdresses" were likely the "jewelled diadems" mentioned in the Belfast ''News-Letter''. The "Fan properties with Feathers" are likely to have been the "long-handled fans of white feathers, mounted in blue and gold" mentioned in the newspaper report.<ref name=":8" />(p. 5, Col. 9a) At the end of the Millward invoice, a "reduction as agreed with M [Mr?] Commelli [sic]" of £1 10''s'' is subtracted from a total of £22 3''s''. No reason for this reduction is given.<ref name=":12" />(2, back) ===== Details for the Children in the Entourage ===== According to the ''Belfast News-Letter'', four children were "in white Assyrian robes, draped with pink shawls."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for "White Cloth Dresses":<ref name=":11" />{{rp|p. 2, back left of invoice}} * "2 Terra Gown draperies with Stars 200 in all" * "2 Cloth fronts embroidered with Square Medallions down centre" * "2 do do [ditto ditto, that is, cloth fronts] embroidered double border down front each side and collar" * "4 Sleeves embroidered Small Medallions" The Burnet & Co. invoice lists 6 yards of "Terra" Silk Fringe, which perhaps was used to trim the "terra draperies," or shawls, made from 3 1/4 yards of "Light Terra Satinette" worn by the children? ===== Details for the Trumpeters in the Entourage ===== According to the ''Belfast News-Letter'', four trumpeters were "in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel."<ref name=":8" />{{rp|p. 5, Col. 9a}} The trumpeters appear to have been dressed as soldiers or military men. According to the B. Burnet invoice, the following was purchased for the trumpeters' costumes:<ref name=":11" />{{rp|p. 1, front of invoice}} * 7 '''units (yards?)''' of purple silk [probably used for shawls] * "2 skirt fronts with border alround [sic]" * "2 sets of Leather Cuarasses [sic] Embroidered front & back" * "4 Sleeves embroidered loop stitch" The Millward invoice lists * 2 Helmets * 2 Centre Pieces [probably for helmets rather than table decorations] ===== Details for the Fan-bearers in the Entourage ===== According to the ''Belfast News-Letter'', four fan-bearers were "attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for the fan bearers's costumes:<ref name=":11" />{{rp|pp. 1–2, front and left-back of invoice}} * "Embroidering 2 Crimson draperies with Stars 334 in all" * "2 Top [?] fronts embroidered & round necks" * "4 Sleeves embroidered long stitch"The Millward invoice lists * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers<ref name=":12" />(2, back) The Burnet & Co. invoice lists 12 yards of "Red Silk Fringe," which perhaps was used to trim the "crimson shawls" or "Crimson draperies," which may have been made from the 5 yards of "Red Satinette." Again, this list suggests two rather than four costumes. === Newspaper Descriptions of the Duchess's Costume === These almost exactly identical descriptions suggest [[Social Victorians/1897 Fancy Dress Ball/anthology#Scissors-and-Paste Journalism|scissors-and-paste journalism]] or a shared primary source: * "The Duchess of Devonshire was a dazzling vision, dressed as 'Zenobia,' in a glistening gold gauze gown, elaborately ornamented with suns and discs, wrought in purple and green gems outlined with gold, and having a large diamond as centre. The space between was fluted with fine silver spangles. This robe was open in front over an under dress of white crépe de chine, delicately worked in crystals, and at each side of the opening on the gold robe were large fan-shaped groups of peacock feathers, worked in multicoloured jewels. '''The corsage''' was to correspond, and had a magnificent girdle of jewels, the train of bright green velvet, hung like a fan, without folds, being fastened at each side of the shoulders by diamond brooches, and caught at the waist with a similar ornament. It was a mass of gorgeous embroidery, carried out in heliotrope velvet, lotus flowers studded with tinted gems, and other devices in terra-cotta and electric blue velvet — all enriched with gold, diamond, and jewelled embroidery — and lined with pale blue satin. The crown worn with this was high, and of filigree gold, surmounted with two horns, each tipped with a large diamond. It was encrusted with large diamonds, rubies, and emeralds, and long chains of pearls fell under the chin and about the head — one magnificent pear-shaped pearl resting on the forehead. Attending the hostess were four children, four fan-bearers, and four trumpeters, all magnificently arrayed in artistically embroidered Assyrian robes, helmets, and other accessories, correct in every detail."<ref>"Duchess of Devonshire's Fancy Ball. A Brilliant Spectacle. Some of the Dresses." London ''Daily News'' Saturday 3 July 1897: 5 [of 10], Col. 6a–6, Col. 1b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000051/18970703/024/0005 and http://www.britishnewspaperarchive.co.uk/viewer/BL/0000051/18970703/024/0006.</ref>{{rp|p. 5, Col. 6a}} * "The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume, supplied by Worth, of Paris. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels, outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jewelled belt. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end, and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls, with a large pear-shaped pearl in the centre falling on the forehead."<ref>“The Ball at Devonshire House. Magnificent Spectacle. Description of the Dresses.” London ''Evening Standard'' 3 July 1897 Saturday: 3 [of 12], Cols. 1a–5b [of 7]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000183/18970703/015/0004.</ref>{{rp|p. 3, Col. 2b}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crepe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crepe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jeweled belt. A gold crown encrusted with emeralds, diamonds, and rubies with a diamond drop at each curved end and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":7" />{{rp|p. 7, Col. 7a}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks’ outspread tails. This opened to show an underdress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls and sprinkled all over with diamonds. The train, which was attached to the shoulders by two slender points and was fastened at the waist with a large diamond ornament, was a green velvet of a lovely shade, and was superbly embroidered in Oriental designs introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, with four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine hidden with a stomacher of real diamonds, rubies and emeralds. Jewelled belt. A gold crown incrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":6">"Ball at Devonshire House." The ''Times'' Saturday 3 July 1897: 12, Cols. 1A–4C ''The Times Digital Archive''. Web. 28 Nov. 2015.</ref>{{rp|p. 12, Col. 3b}} *According to the article in ''The Graphic'', written by [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] though this caption to the Lafayette photograph seems to have been boilerplate and printed in other places, the Duchess of Devonshire wore a "Skirt of gold tissue, embroidered all over with emeralds, sapphires, diamonds, and other jewels outlined with gold. This opened to show an underdress of crème crêpe de chine, embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was green velvet, superbly embroidered in Oriental designs. The bodice was composed of gold tissue, and the front was of crêpe de chine hidden with a stomacher of diamonds, rubies, and emeralds. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre."<ref name=":10">Greville, Violet, Lady. "Devonshire House Ball." The ''Graphic'' Saturday 10 July 1897: 15 [of 24]: Col. 1a–16, Col. 1c. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000057/18970710/019/0015.</ref>{{rp|p. 15, Col. 3b}} *The ''Guernsey Star'' describes first [[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish, Duke of Devonshire]] and then Louisa, Duchess: "The host himself personated Charles V. of Germany in a costume copied from a celebrated picture by Titian, while the hostess was attired with great Oriental magnificence as Zenobia. Her dress was tissue of silver in front [sic], wrought with jewels. The over-dress was cloth of gold magnificently wrought with jewels, and Her Grace wore a bandeau of gold round her head, studded with diamonds, turquoise, and emeralds, and surrounded by hanging chains of superb pearls."<ref>"Duchess of Devonshire's Fancy-Dress Ball. Brilliant Spectacle." The [Guernsey] ''Star'' 6 July 1897, Tuesday: 1 [of 4], Col. 1a–2b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000184/18970706/003/0001.</ref>{{rp|p. 1, Col. 2a}} Gossipy newspaper reports before the ball reported on how costumes were being made. For example, according to the Edinburgh ''Evening News'' on 21 June 1897, less than two weeks before the party, "The ball being a fancy dress one, men as well as women will be able in certain characters to wear jewels. The Duchess of Devonshire, who is to appear as Zenobia, is getting her jewels reset after the antique style."<ref>“The Duchess of Devonshire’s Ball.” Edinburgh ''Evening News'' 21 June 1897, Monday: 4 [of 6], Col. 5c [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000452/18970621/079/0004.</ref> While almost all descriptions of her mention her jewels because they were sewn onto the costume itself, these emphasize her jewelry: * "The Duchess was attired with great Oriental magnificence as Zenobia. Her dress was a tissue of silver, embroidered with gold and jewels, an overmantle of cloth of gold embroidered in the same manner hung from the shoulders, and she wore a bandeau of gold studded with gems, and surrounded by hanging chains of pearls over her elaborate headdress; strings and ropes of jewels and pearls were worn round the neck, and hung down almost to the knees."<ref>“The Duchess of Devonshire’s Ball.” The ''Gentlewoman'' 10 July 1897 Saturday: 32–42 [of 76], Cols. 1a–3c [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0003340/18970710/155/0032. </ref>{{rp|p. 32, Cols. 1c–2a}} * "A wonderfully beautiful dress was that which was worn by the Duchess of Devonshire as Zenobia, Queen of Palmyra. It was of golden tissue, sewn with silver paillettes, and jewelled with diamonds and other precious stones. In front there were silk embroideries, in many vivid shades of colour, and here the golden draperies opened to show a petticoat of white crêpe de chine, embroidered with pearls and gold. The short train was of brilliant green velvet, exquisitely embroidered. One of the Duchess of Devonshire’s beautiful diamond and emerald tiaras had been taken to pieces to form a stomacher, the effect of which was dazzling in its brilliancy. Long chains of pearls and other wonderful jewels were worn with this beautiful dress."<ref>“The Devonshire House Ball. A Brilliant Gathering.” The ''Pall Mall Gazette'' 3 July 1897, Saturday: 7 [of 10], Col. 2a–3a [of 3]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000098/18970703/019/0007.</ref>{{rp|p. 7, Col. 2b}} * In the article about the ball in the ''Graphic'', [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] says, "The Ducal hostess herself elected to appear as Zenobia, Queen of Palmyra, with lavish magnificence, and wearing a corruscation of jewels which must have eclipsed the state of even the all-subduing majesty the Duchess impersonated."<ref name=":10" />{{rp|p. 16, Col. 1a}} *The Duchess was dressed "as Zenobia, Queen of Palmyra, her dress a marvel of soft tissues and exquisite ornament, and her tiara a still greater marvel of the jeweller's art."<ref name=":6" />{{rp|p. 12, Col. 2a}} <ref>"The Duchess of Devonshire’s Historic Ball. Some of the Fancy Costumes." Supplement. The ''Leicester Chronicle and Leicestershire Mercury'' 10 July 1897, Saturday: 11 [of 12], Cols. 4a–b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000173/18970710/141/0011.</ref>{{rp|p. 11, 4a}} === The Historical Zenobia === Zenobia (240 – c. 274) was queen of the Syrian Palmyrene Empire, ruling as regent for her son after her husband's assassination.<ref>{{Cite journal|date=2022-05-03|title=Zenobia|url=https://en.wikipedia.org/w/index.php?title=Zenobia&oldid=1086005949|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Zenobia.</ref> She was the subject of much art in the 19th century, including literature, opera, sculpture, and paintings. Middle-eastern traveller Lady Hester Stanhope (1776–1839) discussed Zenobia in her memoirs, published in 1847.<ref>{{Cite journal|date=2022-03-07|title=Lady Hester Stanhope|url=https://en.wikipedia.org/w/index.php?title=Lady_Hester_Stanhope&oldid=1075838273|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Lady_Hester_Stanhope.</ref> == Demographics == *Nationality: born in Hanover, in what is now Germany<ref name=":0">{{Cite journal|date=2020-07-27|title=Louisa Cavendish, Duchess of Devonshire|url=https://en.wikipedia.org/w/index.php?title=Louisa_Cavendish,_Duchess_of_Devonshire&oldid=969824214|journal=Wikipedia|language=en}}</ref> === Residences === ==== As Duchess of Manchester ==== *Kimbolton Castle, Huntingdonshire *Manchester House, London ==== As Duchess of Devonshire ==== *Devonshire House, London (mid-April until mid-July, for the Season) *Compton Place, Eastbourne (mid-July until 12 August<ref name=":1" />{{rp|p. 32}}) *Bolton Abbey, Yorkshire (12 August until the middle of September<ref name=":1" />{{rp|p. 32}}) *Chatsworth, Derbyshire (middle of September until early Spring<ref name=":1" />{{rp|p. 32}}) *Lismore Castle, County Waterford (early Spring until the middle of April<ref name=":1" />{{rp|p. 32}}) == Family == *Louisa (or Luise) Friederike Auguste Gräfin von Alten Montagu Cavendish (15 January 1832 – 15 November 1911)<ref name=":2" /><ref name=":0" /> *William Drogo Montagu, 7th Duke of Manchester (15 October 1823 – 22 March 1890)<ref name=":3" /><ref>{{Cite journal|date=2020-09-07|title=William Montagu, 7th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=William_Montagu,_7th_Duke_of_Manchester&oldid=977197445|journal=Wikipedia|language=en}}</ref> #George Victor Drogo Montagu, 8th Duke of Manchester (17 June 1853 – 18 August 1892) #Mary Louise [Louisa?] Elizabeth Montagu Douglas-Hamilton Forster (27 December 1854 – 10 February 1934) #Louisa Augusta Beatrice Montagu Acheson (c. 1856 – 3 March 1944) #Charles William Augustus Montagu (23 November 1860 – 10 November 1939) #Alice Maude Olivia Montagu Stanley (15 August 1862 – 23 July 1957) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], 8th Duke of Devonshire (23 July 1833 – 24 March 1908) == Notes and Questions == #As Duchess of Manchester Luise was not invited to the wedding between Bertie and Alix, Victoria's punishment for Luise's having gotten the Duke of Derby to promise her the position of Mistress of the Robes (and then exacting that promise).<ref>Leslie, Anita. ''The Marlborough House Set''. New York: Doubleday, 1973.</ref>{{rp|pp. 47–48}} #"As a young woman she was extremely beautiful; Princess Catherine Radziwill saw her at a reception given by the Empress of Germany and recalls on being introduced to her 'how she struck me as the loveliest creature I had ever set eyes upon. Indeed I have only met three women in my whole existence who could be compared to her.'"<ref name=":1" />{{rp|p. 21}} == Footnotes == {{reflist}} 5jmts06mf576tppzbrru8wyn8hc6wui 2408232 2408231 2022-07-20T22:57:55Z Scogdill 1331941 /* The Duchess and Her Entourage */ wikitext text/x-wiki == Also Known As == *Louise, Duchess of Devonshire *Louisa, Duchess of Manchester *Luise Friederike August Gräfin von Alten *Louisa Montagu *Louise Cavendish *The Double Duchess == Acquaintances, Friends and Enemies == === Friends === *[[Social Victorians/People/Albert Edward, Prince of Wales | Albert Edward, Prince of Wales]] (beginning about 1852) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], Lord Hartington (later 8th Duke of Devonshire) *Daisy, Lady Warwick *Lady Mayoress, Mrs. Benjamin Samuel Faudel-Phillips, 2nd Baronet,<ref>{{Cite journal|date=2020-08-25|title=Faudel-Phillips baronets|url=https://en.wikipedia.org/w/index.php?title=Faudel-Phillips_baronets&oldid=974879290|journal=Wikipedia|language=en}}</ref> presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4">"The Queen's Drawing Room" ''Morning Post'' 25 February 1897 Thursday: 5 [of 10], Col. 5a–7b [of 8]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970225/047/0005.</ref>{{rp|p. 5, Col. 6c}} *Mrs. J. E. Mellor, presented to Victoria by Louisa Cavendish at a Queen's Drawing-room on Wednesday, 24 February 1897 at Buckingham Palace.<ref name=":4" />{{rp|p. 5, Col. 6c}} === Enemies === * Consuelo, Duchess of Marlborough (at least, in 1901)<ref name=":1">Murphy, Sophia. ''The Duchess of Devonshire's Ball''. London: Sidgwick & Jackson, 1984.</ref>{{rp|pp. 31–32}} == Organizations == == Timeline == '''1852 July 22''', Luise Friederike Auguste Gräfin von Alten and William Drogo Montagu married.<ref name=":2">"Luise Friederike Auguste Gräfin von Alten." {{Cite web|url=http://www.thepeerage.com/p10947.htm#i109469|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1863, early, or late 1862''', Louise and Spencer Compton Cavendish began a relationship.<ref name=":1" />{{rp|p. 26}} '''1873 December 10''', Mary Louise Elizabeth Montagu (daughter) and William Douglas-Hamilton married. '''1876 May 22''', Consuelo Iznaga y Clement and George Victor Drogo Montagu (son) married in Grace Church, New York City.<ref>{{Cite journal|date=2020-08-24|title=George Montagu, 8th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=George_Montagu,_8th_Duke_of_Manchester&oldid=974659520|journal=Wikipedia|language=en}}</ref><ref>{{Cite journal|date=2020-07-27|title=Consuelo Montagu, Duchess of Manchester|url=https://en.wikipedia.org/w/index.php?title=Consuelo_Montagu,_Duchess_of_Manchester&oldid=969888488|journal=Wikipedia|language=en}}</ref> '''1876 August 10''', Louisa Augusta Beatrice Montagu (daughter) and Archibald Acheson married. '''1889 January 5''', Alice Maude Olivia Montagu (daughter) and Edward Stanley married. '''1890 March 22''', William Drogo Montagu (7th Duke) died.<ref name=":3">"William Drogo Montagu, 7th Duke of Manchester." {{Cite web|url=http://www.thepeerage.com/p10128.htm#i101274|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1890 November 14''', William Angus Drogo Montagu (grandson) and Helena Zimmerman married secretly, in London.<ref>"Helena Zimmerman." {{Cite web|url=http://www.thepeerage.com/p34555.htm#i345545|title=Person Page|website=www.thepeerage.com|access-date=2020-09-25}}</ref> '''1892 August 16''', Louise Friederike Auguste Gräfin von Alten Montagu and Spencer Compton Cavendish, her second husband, married.<ref name=":2" /> '''1897 July 2, Friday''', Louise Cavendish (#18 on the list of attendees) hosted her famous [[Social Victorians/1897 Fancy Dress Ball| fancy-dress ball]] at Devonshire House in London. '''1897 July 20''', Mary Louise Elizabeth Montagu Douglas-Hamilton and Robert Carnaby Foster married. '''1900 November 14''', William Angus Drogo Montagu and Helena Zimmerman married.<ref>{{Cite journal|date=2020-07-17|title=Helena, Countess of Kintore|url=https://en.wikipedia.org/w/index.php?title=Helena,_Countess_of_Kintore&oldid=968067371|journal=Wikipedia|language=en}}</ref> '''1901 Spring''', Paris, Consuelo Spencer-Churchill, Duchess of Marlborough, describes a meeting with Louise Cavendish in the spring following Queen Victoria's death at the horse racetrack, Longchamps:<blockquote>A renowned character and virtually dictator of what was known as the fast set as opposed to the Victorian, Her Grace was a German aristocrat by birth. She had first been married to the impoverished Duke of Manchester, and when he died had improved her status by marriage to the rich Duke of Devonshire, who waged an undisputed influence in politics. Rumour had her beautiful, but when I knew her she was a raddled old woman, covering her wrinkles with paint and her pate with a brown wig. Her mouth was a red gash and from it, when she saw me, issued a stream of abuse. How could I, she complained, pointing to my white gloves, show so little respect to the memory of a great Queen? What a carefree world we must have lived in, that etiquette even in such small matters could assume so much importance?<ref>Balsan, Consuelo Vanderbilt. ''The Glitter and the Gold: The American Duchess — In Her Own Words''. New York: St. Martin's, 1953.</ref>{{rp|p. 115}}</blockquote> === Annual Events === Every year, as Duchess of Devonshire, Louise held a dance on the night after the Derby at Epsom Downs, which at this point was held on Wednesdays after Easter. == Costume at the Duchess of Devonshire's 2 July 1897 Fancy-dress Ball == [[File:Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra.jpg|thumb|Louise, Duchess of Devonshire as Zenobia, Queen of Palmyra|alt=Louise, Duchess of Devonshire in costume as Zenobia, Queen of Palmyra]] At their fancy-dress ball, Louisa, Duchess of Devonshire sat at Table 1 during the first seating for supper, escorted in to the table by the Prince of Wales.<ref name=":7">"Fancy Dress Ball at Devonshire House." ''Morning Post'' Saturday 3 July 1897: 7 [of 12], Col. 4a–8 Col. 2b. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000174/18970703/054/0007.</ref>{{rp|p. 7, Col. 4c}} Her costume was designed by M. Comelli (Attillo Giuseppe Comelli, 1858–1925, artist and costumier for opera, ballet and theatre in London as well as Europe and the U.S.<ref>{{Cite book|url=https://books.google.com/books?id=SZh2DwAAQBAJ&pg=PT207&lpg=PT207&dq=Attilio+Comelli&source=bl&ots=lFB0If7CwV&sig=ACfU3U1_Ost_lhmMvzMMs6NvuhK5SlRhJw&hl=en&sa=X&ved=2ahUKEwjKlsTw2sH3AhXYAp0JHVIxDWA4KBDoAXoECBAQAw#v=onepage&q=Attilio%20Comelli&f=false|title=Forgotten Designers Costume Designers of American Broadway Revues and Musicals From 1900-1930|last=Unruh|first=Delbert|date=2018-11-06|publisher=Page Publishing Inc|isbn=978-1-64082-758-5|language=en}} N.P.</ref>)<ref name=":5">“The Devonshire House Ball.” The ''Man of Ross'' 10 July 1897, Saturday: 2 [of 8], Col. 4b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0001463/18970710/033/0002.</ref> <ref name=":8">"The Duchess of Devonshire's Fancy Dress Ball. Special Telegram." ''Belfast News-Letter'' Saturday 03 July 1897: 5 [of 8], Col. 9 [of 9]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/BL/0000038/18970703/015/0005.</ref>{{rp|p. 5, Col. 9a}} <ref name=":9">"By One Who Was There." “The Duchess’s Costume Ball.” ''Westminster Gazette'' 03 July 1897 Saturday: 5 [of 8], Cols. 1a–3b [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0002947/18970703/035/0005.</ref> and constructed by the House of Worth. According to Russell Harris,<blockquote>For her costume, the Duchess commissioned Monsieur Comelli (1858-1925), a well-known designer of opera costumes for the London theatre and opera stage, and then had the design made up by Worth of Paris. ''Munsey’s Magazine'' noted “it is safe to say that the Queen of Palmyra never owned such a sumptuous costume in her lifetime.”<ref>Harris, Russell. {{Cite web|url=http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html|title=Louise, Duchess of Devonshire, née Countess von Alten of Hanover (1832-1911), as Zenobia, Queen of Palmyra|website=www.rvondeh.dircon.co.uk|access-date=2022-05-05}} ''Narrated in Calm Prose: Photographs from the V&A's Lafayette Archive of Guests in Costume at the Duchess of Devonshire's Diamond Jubilee Ball, July 1897''. http://www.rvondeh.dircon.co.uk/incalmprose/devonshiredss.html.</ref></blockquote>Lafayette's portrait of "Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester)" in costume is photogravure #5 in the album presented to the Duchess of Devonshire and now in the National Portrait Gallery.<ref>"Devonshire House Fancy Dress Ball (1897): photogravures by Walker & Boutall after various photographers." 1899. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait-list.php?set=515.</ref> The printing on the portrait says, "The Duchess of Devonshire as Zenobia Queen of Palmyra," with a Long S in ''Duchess''.<ref>"Louise Frederica Augusta Cavendish (née von Alten), Duchess of Devonshire (formerly Duchess of Manchester) as Zenobia, Queen of Palmyra." Devonshire House Fancy Dress Ball Album. National Portrait Gallery https://www.npg.org.uk/collections/search/portrait/mw158357/Louise-Frederica-Augusta-Cavendish-ne-von-Alten-Duchess-of-Devonshire-formerly-Duchess-of-Manchester-as-Zenobia-Queen-of-Palmyra.</ref> Often, the V&A Lafayette Archive contains more than one portrait of a sitter for this ball, but the uncropped portrait (above right), which shows the unfinished end of the balustrade in front of the Duchess and the edge of the painted flat behind it, seems to have been the only portrait taken by Lafayette of the Duchess in costume. The copy owned by the National Portrait Gallery in London and the copy included in the album are cropped so that those unfinished edges do not show, but they appear to be from the same photograph. '''[Stuff about entourage below in case you're interested.]''' === The Duchess and Her Entourage === Louise, Duchess of Devonshire was dressed as Zenobia, Queen of Palmyra. Besides the Duke of Devonshire, her retinue included her grandson, [[Social Victorians/People/William Angus Drogo Montagu|William Angus Drago Montagu, 9th Duke of Manchester]], dressed as a Georgian courtier. According to a single source, the Belfast ''News-Letter''<ref name=":8" /> (p. 5, Col. 9a), the rest of her entourage — all in costume — seems to have been made up of the following: * Four children * Four trumpeters * Four fan-bearers Three newspapers — The Belfast ''News-Letter'', the ''Man of Ross'' and the ''Westminster Gazette'' — say that the Duchess's entourage included three groups: children, trumpeters and fan-bearers. Only the Belfast ''News-Letter'' says that each group had four members. These three sources describe the Duchess's retinue and how the people in it were dressed: *"The Duchess of Devonshire was dazzingly [sic] magnificent as 'Zenobia,' arrayed in the glistening fabrics and massive jewels in which artists have delighted to depict the Warrior Queen, the costume in this case being specially designed by the clever French artist, M. Comelli, who was also responsible for the splendid attire of the Queen's suite. This was composed of four children in white Assyrian robes, draped with pink shawls; four trumpeters in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel; and four fan-bearers attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold — a gloriously magnificent pageant."<ref name=":8" />{{rp|p. 5, Col. 9a}} *"The duchess was dressed as Zenobia, in gold cloth, gorgeously embroidered in gold, brilliants, and coloured stones, and opening over an under dress of white crêpe de Chine, worked finely in brilliants. The train of light green velvet was lined with blue, and sumptuously embroidered in jewels and gold, the colouring being particularly artistic. With this dress were worn splendid jewels, and a large horn crown, encrusted with diamonds, emeralds, and rubies. The duchess was attended by a suite of children, trumpeters, and fan-bearers, all picturesquely attired in Assyian [sic] costumes — the whole group being specially designed by M. Comelli."<ref name=":5" /> *"The host was dressed as Charles V. of Germany, in black velvet, satin, and fur; and the Duchess made the most gorgeous of Zenobias, in a gown of gold gauze, and a green velvet train — both a mass of exquisite oriental embroidery. The crown and hanging ropes of pearls, the jewelled girdle, and the train of children, fan-bearers, and trumpeters — all in Babylonish garb — as designed by M. Comelli, made a gloriously imposing and picturesque group."<ref name=":9" /> ==== Details of the Costumes in the Entourage ==== The Archives of the Duke of Devonshire (Devonshire Collections, Chatsworth) has "receipts" or invoices that functioned as receipts for several commercial concerns that were involved in making costumes or accessories for costumes for this ball. They are the following: * B. Burnet & Co. * Arthur Millward, Theatrical Jeweller * M. (Attillo Giuseppe) Comelli * Liberty & Co. * Lafayette, Ltd. * Goldsmith, Pearl & Diamond Merchant, & Silversmith This list of commercial concerns almost certainly cannot be the complete list of all concerns that contributed to the costumes. These are the only receipts or invoices about expenses for the ball, however, that the Chatsworth Archive contains; similar documents were likely not even kept or were destroyed with other papers not retained at some point in time. The business concerns listed above were specialized and likely used for different elements of the costumes. As a theatrical designer, Comelli would have depended on the suppliers he knew and arranged with them for the construction of these costumes. The Chatsworth Archive calls these documents ''receipts'', which indeed they are because they were returned to Devonshire House as receipts for payment. From our perspective, though, they are invoices that contain specifics about what was used to make the costumes. The analysis of these invoices has led to an understanding of what the people who attended the Duchess in her entourage wore and a clearer sense, perhaps, of how many people walked in that entourage. This analysis is based on the items listed on the invoices and their pricing, most of which is included in the section for each invoice, below. '''[blather begins here]''' It is not always clear in the invoices which or how many costumes are being described. If each group contained four members (as the Belfast ''News-Letter'' says<ref name=":8" />(p. 5, Col. 9a)), then other suppliers must have made some of these costumes or other invoices and receipts from these businesses must have existed at that time. The invoices, however, suggest that the Belfast ''News-Letter'' may have been wrong about the number of people in each group, which seem to have contained two rather than four members. [tights, etc., here??] ===== B. Burnet & Co. ===== An invoice and receipt from B. Burnet & Co., held in the Archives of the Duke of Devonshire, has specific information about some of the fabrics, trims and accessories purchased for the costumes of the Duchess's retinue.<ref name=":11">B. Burnet & Co. to Louise, Duchess of Devonshire. Date of invoice 2 and 6 July 1897; postmarked 25 October 1897, for receipt of payment(?). The Devonshire Collections, Chatsworth, Reference number L/109/4(3).</ref> Besides itemizing some costume or accessory elements that seem to be for each group, the invoice also lists items not easy to associate with particular costumes, like the following: * 12 yards of White silk fringe 8in deep<ref name=":11" />{{rp|back left}} * 12 1/2 yards of "wht cloth"<ref name=":11" />{{rp|back left}} * 9 yards of "Selesia"<ref name=":11" />{{rp|back left}} * 2 yards of Canvas<ref name=":11" />{{rp|back right}} * 4 Tan Wool Tights<ref name=":11" />{{rp|back right}} * 2 Tan Boys Tights<ref name=":11" />{{rp|back right}} At this time, we are not sure which costumes these elements were used for. Possibly the white silk fringe and the white cloth would have been used to construct the robes for the children and trumpeters in the entourage. The number of tights suggests that the six costumes on this invoice all included tights. With other elements of the trumpeters' costumes, the Burnet invoice also lists "6 prs Assyrian Buskins." Probably, to a late Victorian, buskins would have been "defensive leggings"<ref>Demmin, Auguste. An illustrated History of Arms and Armour: From the Earliest Period to the Present Time. George Bell, 1894. Google Books https://books.google.com/books?id=ArRCAAAAYAAJ: 106.</ref> laced together and covering the lower leg and often feet of a soldier. To a clothing and military historian, buskins (or greaves) were worn by people in a number of cultures over millennia and varied widely in style and construction. Buskins appear in Assyrian art held at the time by the British Museum. Listing six pairs of buskins suggests that every costume in the Duchess's entrourage included buskins, possibly worn over the tan tights. Besides helmets and cuirasses, the trumpeters may also have worn The Burnet invoice lists "4 Broad Belts," which may have held "4 Skins Fleshers."<ref name=":11" />(p. 1, front of invoice) (A skin flesher is a kind of knife used to separate the skin from the meat in animals.) If each group included only two members, then perhaps the belts and fleshers were worn not only by the trumpeters but also by the fan-bearers. The Millward invoice lists "8 Doz 'Plaques' for Belts'" with a drawing of an upright rectangle with a circle in the middle, which might have been a jewel. Double lines around the rectangle suggest that the plaques were not flat or the metal was not thin. The drawing does not give any ideas about how the plaques were attached to the belts, if they were. A different hand, probably "[L.??] L. Collier," wrote the following sentence at the end of the invoice and receipt, above the postmark:<blockquote>All the above named articles were used for the six [?] dresses made for the Devonshire Ball.<ref name=":11" />(back right)</blockquote>This same hand, signing what is possibly "Floyd Collier," also signed the postmark of the Comelli invoice and receipt. On the Burnet document, this writer, possibly an assistant or employee of the Duchess of Devonshire, says that "six dresses" were made (if in fact, that word is ''six''). (No "Collier" is listed among the staff or servants of the Duke of Devonshire at the end of the 19th century.<ref>"Servants A-H." ''Historic Servants and Staff. Servants and Staff Database''. Retrieved 18 July 2022 https://www.chatsworth.org/media/11528/servants-a-h.pdf.</ref> The invoice appears to itemize materials used for six costumes: two children, two trumpeters and two fan-bearers. ===== Arthur Millward, Theatrical Jeweller ===== An invoice and request for payment from Arthur Millward, Theatrical Jeweller, held in the Archives of Chatsworth House, has more specifics about some of the fabrics, trims and accessories for the costumes of the Duchess's retinue.<ref name=":12">Memorandum. Arthur Millward, Theatrical Jeweller, to Louise, Duchess of Devonshire. Date of itemized invoice 1 July 1897; date of request for payment(?) 27 August 1897. The Devonshire Collections, Chatsworth, Reference number L/109/4(?).</ref> This invoice lists the following, which could have been used in any of the costumes for the entourage: * 8 Doz 'Plaques' for Belts * 4 Large Armlets * 4 Bracelets * 8 Armlets<ref name=":12" />(2, back) Because Millward was a Theatrical Jeweller, it seems likely that most (if not all) of the items listed on the invoice were made of metal and the jewels mentioned were artificial, made of glass or paste. Other items on the invoice seem to belong to the costumes of the trumpeters, which the Belfast ''News-Letter'' says included helmets: * 2 Helmets * 2 Centre pieces The Millward invoice shows tiny line drawings next to the words ''2 Helmets'' and ''2 Centre pieces''. These drawings suggest that the Centre pieces were attached to the helmets rather than being anything that would have been put on a table as decoration. Other items seem to belong to the costumes of the fan-bearers: * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers The "Pearl & Gold Headdresses" were likely the "jewelled diadems" mentioned in the Belfast ''News-Letter''. The "Fan properties with Feathers" are likely to have been the "long-handled fans of white feathers, mounted in blue and gold" mentioned in the newspaper report.<ref name=":8" />(p. 5, Col. 9a) At the end of the Millward invoice, a "reduction as agreed with M [Mr?] Commelli [sic]" of £1 10''s'' is subtracted from a total of £22 3''s''. No reason for this reduction is given.<ref name=":12" />(2, back) ===== Details for the Children in the Entourage ===== According to the ''Belfast News-Letter'', four children were "in white Assyrian robes, draped with pink shawls."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for "White Cloth Dresses":<ref name=":11" />{{rp|p. 2, back left of invoice}} * "2 Terra Gown draperies with Stars 200 in all" * "2 Cloth fronts embroidered with Square Medallions down centre" * "2 do do [ditto ditto, that is, cloth fronts] embroidered double border down front each side and collar" * "4 Sleeves embroidered Small Medallions" The Burnet & Co. invoice lists 6 yards of "Terra" Silk Fringe, which perhaps was used to trim the "terra draperies," or shawls, made from 3 1/4 yards of "Light Terra Satinette" worn by the children? ===== Details for the Trumpeters in the Entourage ===== According to the ''Belfast News-Letter'', four trumpeters were "in white cloth robes, embroidered in subdued tones of silks, with a purple shawl draped over, beautifully ornamented with embroidery, and wearing fringed steel helmets and leather cuirasses embossed in steel."<ref name=":8" />{{rp|p. 5, Col. 9a}} The trumpeters appear to have been dressed as soldiers or military men. According to the B. Burnet invoice, the following was purchased for the trumpeters' costumes:<ref name=":11" />{{rp|p. 1, front of invoice}} * 7 '''units (yards?)''' of purple silk [probably used for shawls] * "2 skirt fronts with border alround [sic]" * "2 sets of Leather Cuarasses [sic] Embroidered front & back" * "4 Sleeves embroidered loop stitch" The Millward invoice lists * 2 Helmets * 2 Centre Pieces [probably for helmets rather than table decorations] ===== Details for the Fan-bearers in the Entourage ===== According to the ''Belfast News-Letter'', four fan-bearers were "attired in pale blue robes, with crimson shawls, enriched with gold and jewelled embroidery, adorned with jewelled diadems, and holding long-handled fans of white feathers, mounted in blue and gold."<ref name=":8" />{{rp|p. 5, Col. 9a}} According to the B. Burnet invoice, the following was purchased for the fan bearers's costumes:<ref name=":11" />{{rp|pp. 1–2, front and left-back of invoice}} * "Embroidering 2 Crimson draperies with Stars 334 in all" * "2 Top [?] fronts embroidered & round necks" * "4 Sleeves embroidered long stitch"The Millward invoice lists * 2 Pearl & Gold Headdresses * 2 Fan properties with Feathers<ref name=":12" />(2, back) The Burnet & Co. invoice lists 12 yards of "Red Silk Fringe," which perhaps was used to trim the "crimson shawls" or "Crimson draperies," which may have been made from the 5 yards of "Red Satinette." Again, this list suggests two rather than four costumes. === Newspaper Descriptions of the Duchess's Costume === These almost exactly identical descriptions suggest [[Social Victorians/1897 Fancy Dress Ball/anthology#Scissors-and-Paste Journalism|scissors-and-paste journalism]] or a shared primary source: * "The Duchess of Devonshire was a dazzling vision, dressed as 'Zenobia,' in a glistening gold gauze gown, elaborately ornamented with suns and discs, wrought in purple and green gems outlined with gold, and having a large diamond as centre. The space between was fluted with fine silver spangles. This robe was open in front over an under dress of white crépe de chine, delicately worked in crystals, and at each side of the opening on the gold robe were large fan-shaped groups of peacock feathers, worked in multicoloured jewels. '''The corsage''' was to correspond, and had a magnificent girdle of jewels, the train of bright green velvet, hung like a fan, without folds, being fastened at each side of the shoulders by diamond brooches, and caught at the waist with a similar ornament. It was a mass of gorgeous embroidery, carried out in heliotrope velvet, lotus flowers studded with tinted gems, and other devices in terra-cotta and electric blue velvet — all enriched with gold, diamond, and jewelled embroidery — and lined with pale blue satin. The crown worn with this was high, and of filigree gold, surmounted with two horns, each tipped with a large diamond. It was encrusted with large diamonds, rubies, and emeralds, and long chains of pearls fell under the chin and about the head — one magnificent pear-shaped pearl resting on the forehead. Attending the hostess were four children, four fan-bearers, and four trumpeters, all magnificently arrayed in artistically embroidered Assyrian robes, helmets, and other accessories, correct in every detail."<ref>"Duchess of Devonshire's Fancy Ball. A Brilliant Spectacle. Some of the Dresses." London ''Daily News'' Saturday 3 July 1897: 5 [of 10], Col. 6a–6, Col. 1b. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000051/18970703/024/0005 and http://www.britishnewspaperarchive.co.uk/viewer/BL/0000051/18970703/024/0006.</ref>{{rp|p. 5, Col. 6a}} * "The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume, supplied by Worth, of Paris. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels, outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jewelled belt. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end, and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls, with a large pear-shaped pearl in the centre falling on the forehead."<ref>“The Ball at Devonshire House. Magnificent Spectacle. Description of the Dresses.” London ''Evening Standard'' 3 July 1897 Saturday: 3 [of 12], Cols. 1a–5b [of 7]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0000183/18970703/015/0004.</ref>{{rp|p. 3, Col. 2b}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks' outspread tails. This opened to show an under-dress of cream crepe de chine, delicately embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was attached to the shoulders by two slender points, and was fastened at the waist with a large diamond ornament. It was of green velvet of a lovely shade, and was superbly embroidered in Oriental designs, introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, in four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crepe de chine, hidden with a stomacher of real diamonds, rubies, and emeralds, and there was a jeweled belt. A gold crown encrusted with emeralds, diamonds, and rubies with a diamond drop at each curved end and two upstanding white ostrich feathers in the centre, and round the front were festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":7" />{{rp|p. 7, Col. 7a}} *"The Duchess of Devonshire, as Zenobia, Queen of Palmyra, wore a magnificent costume. The skirt of gold tissue was embroidered all over in a star-like design in emeralds, sapphires, diamonds, and other jewels outlined with gold, the corners where it opened in front being elaborately wrought in the same jewels and gold to represent peacocks’ outspread tails. This opened to show an underdress of cream crêpe de chine, delicately embroidered in silver, gold, and pearls and sprinkled all over with diamonds. The train, which was attached to the shoulders by two slender points and was fastened at the waist with a large diamond ornament, was a green velvet of a lovely shade, and was superbly embroidered in Oriental designs introducing the lotus flower in rubies, sapphires, amethysts, emeralds, and diamonds, with four borderings on contrasting grounds, separated with gold cord. The train was lined with turquoise satin. The bodice was composed of gold tissue to match the skirt, and the front was of crêpe de chine hidden with a stomacher of real diamonds, rubies and emeralds. Jewelled belt. A gold crown incrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre falling on the forehead."<ref name=":6">"Ball at Devonshire House." The ''Times'' Saturday 3 July 1897: 12, Cols. 1A–4C ''The Times Digital Archive''. Web. 28 Nov. 2015.</ref>{{rp|p. 12, Col. 3b}} *According to the article in ''The Graphic'', written by [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] though this caption to the Lafayette photograph seems to have been boilerplate and printed in other places, the Duchess of Devonshire wore a "Skirt of gold tissue, embroidered all over with emeralds, sapphires, diamonds, and other jewels outlined with gold. This opened to show an underdress of crème crêpe de chine, embroidered in silver, gold, and pearls, and sprinkled all over with diamonds. The train was green velvet, superbly embroidered in Oriental designs. The bodice was composed of gold tissue, and the front was of crêpe de chine hidden with a stomacher of diamonds, rubies, and emeralds. A gold crown encrusted with emeralds, diamonds, and rubies, with a diamond drop at each curved end and two upstanding white ostrich feathers in the middle, and round the front festoons of pearls with a large pear-shaped pearl in the centre."<ref name=":10">Greville, Violet, Lady. "Devonshire House Ball." The ''Graphic'' Saturday 10 July 1897: 15 [of 24]: Col. 1a–16, Col. 1c. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000057/18970710/019/0015.</ref>{{rp|p. 15, Col. 3b}} *The ''Guernsey Star'' describes first [[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish, Duke of Devonshire]] and then Louisa, Duchess: "The host himself personated Charles V. of Germany in a costume copied from a celebrated picture by Titian, while the hostess was attired with great Oriental magnificence as Zenobia. Her dress was tissue of silver in front [sic], wrought with jewels. The over-dress was cloth of gold magnificently wrought with jewels, and Her Grace wore a bandeau of gold round her head, studded with diamonds, turquoise, and emeralds, and surrounded by hanging chains of superb pearls."<ref>"Duchess of Devonshire's Fancy-Dress Ball. Brilliant Spectacle." The [Guernsey] ''Star'' 6 July 1897, Tuesday: 1 [of 4], Col. 1a–2b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000184/18970706/003/0001.</ref>{{rp|p. 1, Col. 2a}} Gossipy newspaper reports before the ball reported on how costumes were being made. For example, according to the Edinburgh ''Evening News'' on 21 June 1897, less than two weeks before the party, "The ball being a fancy dress one, men as well as women will be able in certain characters to wear jewels. The Duchess of Devonshire, who is to appear as Zenobia, is getting her jewels reset after the antique style."<ref>“The Duchess of Devonshire’s Ball.” Edinburgh ''Evening News'' 21 June 1897, Monday: 4 [of 6], Col. 5c [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000452/18970621/079/0004.</ref> While almost all descriptions of her mention her jewels because they were sewn onto the costume itself, these emphasize her jewelry: * "The Duchess was attired with great Oriental magnificence as Zenobia. Her dress was a tissue of silver, embroidered with gold and jewels, an overmantle of cloth of gold embroidered in the same manner hung from the shoulders, and she wore a bandeau of gold studded with gems, and surrounded by hanging chains of pearls over her elaborate headdress; strings and ropes of jewels and pearls were worn round the neck, and hung down almost to the knees."<ref>“The Duchess of Devonshire’s Ball.” The ''Gentlewoman'' 10 July 1897 Saturday: 32–42 [of 76], Cols. 1a–3c [of 3]. ''British Newspaper Archive'' https://www.britishnewspaperarchive.co.uk/viewer/bl/0003340/18970710/155/0032. </ref>{{rp|p. 32, Cols. 1c–2a}} * "A wonderfully beautiful dress was that which was worn by the Duchess of Devonshire as Zenobia, Queen of Palmyra. It was of golden tissue, sewn with silver paillettes, and jewelled with diamonds and other precious stones. In front there were silk embroideries, in many vivid shades of colour, and here the golden draperies opened to show a petticoat of white crêpe de chine, embroidered with pearls and gold. The short train was of brilliant green velvet, exquisitely embroidered. One of the Duchess of Devonshire’s beautiful diamond and emerald tiaras had been taken to pieces to form a stomacher, the effect of which was dazzling in its brilliancy. Long chains of pearls and other wonderful jewels were worn with this beautiful dress."<ref>“The Devonshire House Ball. A Brilliant Gathering.” The ''Pall Mall Gazette'' 3 July 1897, Saturday: 7 [of 10], Col. 2a–3a [of 3]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000098/18970703/019/0007.</ref>{{rp|p. 7, Col. 2b}} * In the article about the ball in the ''Graphic'', [[Social Victorians/People/Lady Violet Greville|Lady Violet Greville]] says, "The Ducal hostess herself elected to appear as Zenobia, Queen of Palmyra, with lavish magnificence, and wearing a corruscation of jewels which must have eclipsed the state of even the all-subduing majesty the Duchess impersonated."<ref name=":10" />{{rp|p. 16, Col. 1a}} *The Duchess was dressed "as Zenobia, Queen of Palmyra, her dress a marvel of soft tissues and exquisite ornament, and her tiara a still greater marvel of the jeweller's art."<ref name=":6" />{{rp|p. 12, Col. 2a}} <ref>"The Duchess of Devonshire’s Historic Ball. Some of the Fancy Costumes." Supplement. The ''Leicester Chronicle and Leicestershire Mercury'' 10 July 1897, Saturday: 11 [of 12], Cols. 4a–b [of 7]. ''British Newspaper Archive'' http://www.britishnewspaperarchive.co.uk/viewer/bl/0000173/18970710/141/0011.</ref>{{rp|p. 11, 4a}} === The Historical Zenobia === Zenobia (240 – c. 274) was queen of the Syrian Palmyrene Empire, ruling as regent for her son after her husband's assassination.<ref>{{Cite journal|date=2022-05-03|title=Zenobia|url=https://en.wikipedia.org/w/index.php?title=Zenobia&oldid=1086005949|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Zenobia.</ref> She was the subject of much art in the 19th century, including literature, opera, sculpture, and paintings. Middle-eastern traveller Lady Hester Stanhope (1776–1839) discussed Zenobia in her memoirs, published in 1847.<ref>{{Cite journal|date=2022-03-07|title=Lady Hester Stanhope|url=https://en.wikipedia.org/w/index.php?title=Lady_Hester_Stanhope&oldid=1075838273|journal=Wikipedia|language=en}} https://en.wikipedia.org/wiki/Lady_Hester_Stanhope.</ref> == Demographics == *Nationality: born in Hanover, in what is now Germany<ref name=":0">{{Cite journal|date=2020-07-27|title=Louisa Cavendish, Duchess of Devonshire|url=https://en.wikipedia.org/w/index.php?title=Louisa_Cavendish,_Duchess_of_Devonshire&oldid=969824214|journal=Wikipedia|language=en}}</ref> === Residences === ==== As Duchess of Manchester ==== *Kimbolton Castle, Huntingdonshire *Manchester House, London ==== As Duchess of Devonshire ==== *Devonshire House, London (mid-April until mid-July, for the Season) *Compton Place, Eastbourne (mid-July until 12 August<ref name=":1" />{{rp|p. 32}}) *Bolton Abbey, Yorkshire (12 August until the middle of September<ref name=":1" />{{rp|p. 32}}) *Chatsworth, Derbyshire (middle of September until early Spring<ref name=":1" />{{rp|p. 32}}) *Lismore Castle, County Waterford (early Spring until the middle of April<ref name=":1" />{{rp|p. 32}}) == Family == *Louisa (or Luise) Friederike Auguste Gräfin von Alten Montagu Cavendish (15 January 1832 – 15 November 1911)<ref name=":2" /><ref name=":0" /> *William Drogo Montagu, 7th Duke of Manchester (15 October 1823 – 22 March 1890)<ref name=":3" /><ref>{{Cite journal|date=2020-09-07|title=William Montagu, 7th Duke of Manchester|url=https://en.wikipedia.org/w/index.php?title=William_Montagu,_7th_Duke_of_Manchester&oldid=977197445|journal=Wikipedia|language=en}}</ref> #George Victor Drogo Montagu, 8th Duke of Manchester (17 June 1853 – 18 August 1892) #Mary Louise [Louisa?] Elizabeth Montagu Douglas-Hamilton Forster (27 December 1854 – 10 February 1934) #Louisa Augusta Beatrice Montagu Acheson (c. 1856 – 3 March 1944) #Charles William Augustus Montagu (23 November 1860 – 10 November 1939) #Alice Maude Olivia Montagu Stanley (15 August 1862 – 23 July 1957) *[[Social Victorians/People/Spencer Compton Cavendish|Spencer Compton Cavendish]], 8th Duke of Devonshire (23 July 1833 – 24 March 1908) == Notes and Questions == #As Duchess of Manchester Luise was not invited to the wedding between Bertie and Alix, Victoria's punishment for Luise's having gotten the Duke of Derby to promise her the position of Mistress of the Robes (and then exacting that promise).<ref>Leslie, Anita. ''The Marlborough House Set''. New York: Doubleday, 1973.</ref>{{rp|pp. 47–48}} #"As a young woman she was extremely beautiful; Princess Catherine Radziwill saw her at a reception given by the Empress of Germany and recalls on being introduced to her 'how she struck me as the loveliest creature I had ever set eyes upon. Indeed I have only met three women in my whole existence who could be compared to her.'"<ref name=":1" />{{rp|p. 21}} == Footnotes == {{reflist}} 66adiwvx29qfhsdvtumruphkvcx2pxd 0 269289 2408162 2408161 2022-07-20T12:03:10Z Maxim Masiutin 2902665 /* Clinical Significance */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref>Both enzymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} tukhd0vjin5slh1kit9uotjz5h4bu89 2408163 2408162 2022-07-20T12:06:13Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref>Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} evbxs80yteac5zvrp6m7j52imsic6je 2408164 2408163 2022-07-20T12:07:42Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref>Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ehu2t1rydjav8r9v5rr8v4e9ox68kkx 2408165 2408164 2022-07-20T12:09:04Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === It was discovered in the 1950s that both 11OHA4 and 11KA4, which were known to be products of the human adrenal, had negligible androgenic activity, however, they have been written off as a dead-end product of adrenal steroidogenesis, and their role as substrates to potent androgens has been overlooked until 2010s.<ref name="pmid27519632" /><ref name="pmid30959151" /> 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} lc8x59rd7vppiwlx3bpr541phqvtetw 2408167 2408165 2022-07-20T12:17:39Z Maxim Masiutin 2902665 removed repetition wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11KT and 11DHT are 11-oxo forms of T and DHT, respectively, and having similar potency, as discovered by Pretorius et al. in 2016.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248"/> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} e7f60epnmxnap8utp180zbaknxye52q 2408168 2408167 2022-07-20T12:20:43Z Maxim Masiutin 2902665 removed repetitions wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} mhubqv63kuw1n9jgglbox7200tv38kr 2408169 2408168 2022-07-20T12:23:36Z Maxim Masiutin 2902665 ordered list was broken wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of androstenedione to testosterone) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} jzx5kl5scy1oek0hyof8d3rjf8rvtii 2408170 2408169 2022-07-20T12:29:24Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} q3va5kydmrxkkwv3y465crbzajmc98q 2408171 2408170 2022-07-20T12:31:28Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert P4, 17-OHP, A4 and T - Δ⁴ steroids.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} nu48p35c84opk6pivdxl3ipl3ndln7z 2408172 2408171 2022-07-20T12:32:19Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T but unlike testosterone, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to testosterone. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} n4h7jly1xi3iis618eb1nzaiywlx0zf 2408175 2408172 2022-07-20T12:43:18Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. === ??? === Since CYP11B1 and CYP11B2 11-oxygenated androgens follow the circadian rhythm of cortisol but correlate very weakly with testosterone, which further supports their adrenal origin and ACTH governance.<ref name="pmid34867794" /><ref name="pmid34324429">{{cite journal|last1=Turcu|first1=Adina F.|last2=Zhao|first2=Lili|last3=Chen|first3=Xuan|last4=Yang|first4=Rebecca|last5=Rege|first5=Juilee|last6=Rainey|first6=William E.|last7=Veldhuis|first7=Johannes D.|last8=Auchus|first8=Richard J.|year=2021|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men|journal=Eur J Endocrinol|volume=185|issue=4|pages=K1–K6|doi=10.1530/EJE-21-0348|pmc=8826489|pmid=34324429|pmc-embargo-date=August 27, 2022}}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878" /> ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 6nohseqrqn8maxpegdmdijb5qwlf4up 2408176 2408175 2022-07-20T12:44:11Z Maxim Masiutin 2902665 /* Clinical Significance */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378" /> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid27428878">{{cite journal|last1=Imamichi|first1=Yoshitaka|last2=Yuhki|first2=Koh-Ichi|last3=Orisaka|first3=Makoto|last4=Kitano|first4=Takeshi|last5=Mukai|first5=Kuniaki|last6=Ushikubi|first6=Fumitaka|last7=Taniguchi|first7=Takanobu|last8=Umezawa|first8=Akihiro|last9=Miyamoto|first9=Kaoru|year=2016|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads|journal=J Clin Endocrinol Metab|volume=101|issue=10|pages=3582–3591|doi=10.1210/jc.2016-2311|pmid=27428878|last10=Yazawa|first10=Takashi}}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210" /><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794">{{cite journal|last1=Turcu|first1=Adina F.|last2=Mallappa|first2=Ashwini|last3=Nella|first3=Aikaterini A.|last4=Chen|first4=Xuan|last5=Zhao|first5=Lili|last6=Nanba|first6=Aya T.|last7=Byrd|first7=James Brian|last8=Auchus|first8=Richard J.|last9=Merke|first9=Deborah P.|year=2021|title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency|journal=Front Endocrinol (Lausanne)|volume=12|issue=|pages=751191|doi=10.3389/fendo.2021.751191|pmc=8636728|pmid=34867794|doi-access=free}}</ref> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} tdtvhuayg6xa9anyp65cpdmpzbrpz55 2408177 2408176 2022-07-20T13:00:19Z Maxim Masiutin 2902665 fixed broken references wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, citing inconsistent results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations such as T, A4, and DHEA, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ifsaggmk3fopj0vjtjte1jdexvumwq7 2408178 2408177 2022-07-20T13:37:24Z Maxim Masiutin 2902665 /* Castration-Resistant Prostate Cancer */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 73do3f9kz3s62p90ebejcg3756b6xvh 2408181 2408178 2022-07-20T13:50:36Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} cod490ivd6zblq84vbpc8t8h7lu34uh 2408182 2408181 2022-07-20T15:13:14Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref>The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ovgc9hxchmb6pcworhvx6mx0p7t0623 2408183 2408182 2022-07-20T15:29:01Z Maxim Masiutin 2902665 /* Biological Role of 11-Oxygenated Androgens */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that testosterone (T) and 5α-dihydrotestosterone (DHT) are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} cjneqkl2yhkgzfb4diujj5c2v2rj1jb 2408191 2408183 2022-07-20T17:03:50Z Maxim Masiutin 2902665 /* Hyperandrogenism */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and testosterone; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} bjy311cb8qa93982achnuvc4jyk7uff 2408192 2408191 2022-07-20T17:04:24Z Maxim Masiutin 2902665 /* Backdoor Pathways to 5α-Dihydrotestosterone */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of testosterone; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from testosterone.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ixbx776gajpmyv03aruqaocap3fmik2 2408194 2408192 2022-07-20T17:04:55Z Maxim Masiutin 2902665 /* 11-Oxygenated Androgen Pathways */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1 according to comprehensive sources.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> Indication of this particular isozyme seems to be based on Frederiksen et al. in 1971,<ref>{{Cite journal|last=Frederiksen|first=D.W.|last2=Wilson|first2=Jean D.|date=1971-04|title=Partial Characterization of the Nuclear Reduced Nicotinamide Adenine Dinucleotide Phosphate: Δ4-3-Ketosteroid 5α-Oxidoreductase of Rat Prostate|url=https://linkinghub.elsevier.com/retrieve/pii/S0021925818623282|journal=Journal of Biological Chemistry|language=en|volume=246|issue=8|pages=2584–2593|doi=10.1016/S0021-9258(18)62328-2}}</ref> but recent articles suggest that SRD5A2 may also catalyze this transformation in certain contexts.<ref name="pmid28774496" /> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} sdgegrsau4coxi7gefjl503v0n0str6 2408204 2408194 2022-07-20T19:57:35Z Maxim Masiutin 2902665 /* 17α-Hydroxyprogesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 4erhriwl07h9nksv6if8hlrk64od48n 2408205 2408204 2022-07-20T19:58:17Z Maxim Masiutin 2902665 /* Progesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this route is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} mkqzuepmunwak8lee6snb97sxtup7ir 2408207 2408205 2022-07-20T20:04:48Z Maxim Masiutin 2902665 /* 17α-Hydroxyprogesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and CYP17A1 are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of cytochrome P450 17A1 (CYP17A1). This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} rz1hkmj9zbfp3mrwbpuo9t9wr4udxbg 2408208 2408207 2022-07-20T20:05:28Z Maxim Masiutin 2902665 /* Progesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and CYP17A1 are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} gcfshn05mlo1ssc156s5engm46p89cp 2408209 2408208 2022-07-20T20:06:41Z Maxim Masiutin 2902665 /* 17α-Hydroxyprogesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980"/> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} sx8w5ivo62fo4qknhsfbth633lm31ao 2408211 2408209 2022-07-20T20:08:29Z Maxim Masiutin 2902665 wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378" /> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 38gc4cvlv3p4c7zbxa45ipoainv8mok 2408213 2408211 2022-07-20T20:10:01Z Maxim Masiutin 2902665 wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1/SRD5A2.<ref name="pmid31626910"/> 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 0e7u0s7221u59zfno73o8jm5ibmyc71 2408221 2408213 2022-07-20T20:35:04Z Maxim Masiutin 2902665 wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ng6ouh27piw0ryth4r0nsi4inrb46g0 2408223 2408221 2022-07-20T21:07:02Z Maxim Masiutin 2902665 wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460"/><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} jfjs408v1rroflfjdqk3oumsair8htp 2408224 2408223 2022-07-20T21:07:35Z Maxim Masiutin 2902665 /* 17α-Hydroxyprogesterone Pathway */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] This pathway will only function when both 5α-reductase and steroid 17α-hydroxylase/17,20-lyase (CYP17A1) are expressed in the same tissue.<ref name="pmid15519890"/><ref name="pmid25379460">{{cite journal |title=Steroid hormone synthetic pathways in prostate cancer |journal=Transl Androl Urol |volume=2 |issue=3 |pages=212–227 |date=September 2013 |pmid=25379460 |pmc=4219921 |doi=10.3978/j.issn.2223-4683.2013.09.16}}</ref> The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 05cbrtwnnw6t1bszm0icx15tokawyjl 2408264 2408224 2022-07-21T04:18:00Z Maneesh 2723004 /* 17α-Hydroxyprogesterone Pathway */ per discussion wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways.These 19-carbon steroids contain either a hydroxy group (-OH) or an oxo group (=O) covalently bound to the carbon atom at position 11 (see Figure 1). As noted earlier, 11KT and 11DHT are the most potent members of this class. The 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4) , also known as adrenosterone, are not regarded as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} e0mad5o73o6qq6p82c2b9pm1g8qbt1e 2408266 2408264 2022-07-21T04:20:16Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways. As noted earlier, 11KT and 11DHT are the most potent members of this class while 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4, also known as adrenosterone), are not considered as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/>{{ordered list |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT.}} These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: {{ordered list |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} is4i3rmerouvpshnm4mpauvl2ovwayc 2408267 2408266 2022-07-21T04:21:14Z Maneesh 2723004 /* 11-Oxygenated Androgen Pathways */ removing list template, can't edit visually wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent and clinically relevant 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways. As noted earlier, 11KT and 11DHT are the most potent members of this class while 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4, also known as adrenosterone), are not considered as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. There are several routes that may lead to the production of 11-oxygenated androgens, however, 11β-hydroxylation of a steroid substrate is the initial step in all cases.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and 17β-hydroxysteroid dehydrogenase type 5 (encoded by AKR1C3) catalyses the conversion of 11KA4 to 11KT, even significantly more efficiently than the conversion of A4 to T.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> It is believed that more 11KT is produced from 11KA4 than from 11OHT.<ref name="pmid23386646" /><ref name="pmid29936123" /> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> |First, 11-oxygenated androgens, 11OHA4 and 11β-hydroxytestosterone (11OHT), are produced (by the CYP11B1/CYP11B2 isozymes) from A4 and T respectively. |Then, there can be the following reactions: 11OHA4 and 11OHT can be converted by HSD11B2 in the production of their 11-oxo forms, 4-androstene-3,11,17-trione (better known as 11-ketoandrostenedione (11KA4)) and 4-androsten-17β-ol-3,11-dione (better known as 11-ketotestosterone (11KT)), respectively. These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> |Further adding to the complexity of these reactions is the fact that 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can convert all of the 11-oxo androgens back to the 11-hydroxy androgens. Like with cortisol and cortisone, there seems to be a continuous interconversion between the 11-hydroxy and 11-oxo forms of androgens catalyzed by HSD11B1 and HSD11B2.<ref name="pmid23856005" /> |There may be a conversion of 11OHA4, 11KA4, 11OHT and 11KT by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (also known as 11β-hydroxydihydrotestosterone (11OHDHT)) and 5α-androstan-17β-ol-3,11-dione also known as 11-ketodihydrotestosterone (11KDHT), respectively. As for 5α-reduction of 11KT to 11KDHT, while Storbeck et al. in a 2013 study demonstrated that 11KT and other 11-oxygenated androgens are substrates for SRD5A1 and SRD5A2,<ref name="pmid23856005" /> that study did not perform full kinetic analyses. The 2020 study by Barnard et al. showed that SRD5A1 does not efficiently catalyze the 5α-reduction of 11KT or 11KA4<ref name="pmid32629108" /> confirming that 11KT may be the most relevant active 11-oxygenated androgen given the abundant peripheral expression of SRD5A2. While this does not rule out the potential for 11KDHT to be produced by SRD5A2 (or to a lesser degree by SRD5A1) in specific tissues, current evidence suggests that the emphasis should put to the relevance of 11KT rather than 11KDHT.<ref name="pmid32629108" /> |11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone (11OHAST)), 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone (11KAST)), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). However, this reaction is reversible and so these inactive androgens can be reactivated putting 11KDHT and 11OHT back into the system. |These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646"/> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646"/><ref name="pmid29936123"/> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123"/>, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} ng63w0tofypw93qlex28vhtofme6oq7 2408304 2408267 2022-07-21T05:34:13Z Maneesh 2723004 /* From Androstenedione or Testosterone Towards 11-Oxygenated Androgens */ lots of cutting of sentences that are too vague ("back into the system") or are not clearly motivated wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). Full enzyme names can be found in the Abbreviations section. === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways. As noted earlier, 11KT and 11DHT are the most potent members of this class while 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4, also known as adrenosterone), are not considered as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. The first step in all routes to 11-oxygenated androgens is the 11β-hydroxylation of a steroid precursor.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. HSD11B2 converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and AKR1C3 catalyses the conversion of 11KA4 to 11KT.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> The initial 11β-hydroxylation of A4 and T to (respectively) 11OHA4 and 11β-hydroxytestosterone (11OHT) via CYP11B1 and CYP11B2. 11OHA4 and 11OHT can then be converted (via HSD11B2) to their 11-oxo forms, 4-androstene-3,11,17-trione (11KA4, since it is also known as 11-ketoandrostenedione) and 4-androsten-17β-ol-3,11-dione (11KT, since it is also known as 11-ketotestosterone). These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> HSD11B1 can catalyze the reverse reaction of 11-oxo androgens back to the 11-hydroxy androgens.<ref name="pmid23856005" /> Each of 11OHA4, 11KA4, 11OHT and 11KT can be reduced (via SRD5A1 and SRD5A2) 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (11OHDHT, since it is also known as 11β-hydroxydihydrotestosterone) and 11KDHT, respectively. 11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (11OHAST, since it also known as 11β-hydroxyandrosterone), 5α-androstan-3α-ol-11,17-dione (11KAST, since it is also known as 11-ketoandrosterone), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by AKR1C2 and AKR1C4. These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646" /> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646" /><ref name="pmid29936123" /> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123" />, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The initial step in the production of 11-oxygenated androgens from the pregnanes is that of P4 to 11β-hydroxyprogesterone (11OHP4), also known as 21-deoxycorticosterone<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1/CYP11B2. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: |The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by 5α-reductase isozymes, SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone (11KDHP4)), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). |11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). |3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561"/> |11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. |11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}} These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964"/> in a 2021 review, can be outlined as shown on Figure 4. <!-- <pre> P4 → 11OHP4 ⇄ 11KP4 ↓ ↓ 11OHDHP4 ⇄ 11KDHP4 ⇅ ⇅ 3,11diOH-DHP4 ⇄ ALF ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from progesterone (P4) towards 11-oxygenated androgens)}<pre> 17-OHP → 21dF ⇄ 21dE ↓ ↓ 11OHPdione ⇄ 11KPdione ⇅ ⇅ 11OHPdiol ⇄ 11KPdiol ↓ ↓ 11OHAST ⇄ 11KAST ⇄ 11K-5αdione ⇅ ⇅ 11K-3αdiol ⇄ 11KDHT ⇄ 11OHDHT </pre>^{(the route from 17α-hydroxyprogesterone (17-OHP) towards 11-oxygenated androgens)} --> The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid33539964"/> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707"/><ref name="pmid23685396"/><ref name="pmid30825506"/> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} de9ff1yrj7z0dmp2no2hwpnwsm3230r 2408324 2408304 2022-07-21T06:18:33Z Maneesh 2723004 /* From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens */ saving progress...this is all very very dense and hard to follow wikitext text/x-wiki {{Article info | first1 = Maxim G | last1 = Masiutin | orcid1 = 0000-0002-8129-4500 | correspondence1 = maxim@masiutin.com | first2 = Maneesh K | last2 = Yadav | orcid2 = 0000-0002-4584-7606 | submitted = 4/22/2022 | contributors = | et_al = <!-- * The Wikipedia source page was https://en.wikipedia.org/wiki/Androgen_backdoor_pathway * No other people except the authors of the present article have contributed to the source page until this article was forked from that page on October 22, 2020 * When I added the "w1" attribute to the "Article info" box, the "et al." appears. The "et_al = false" attribute does not seem to work. There should be no "et al.". I have not found any way to remove the "et al." rather than removing the "w1" attribute. * Only when I remove both the "w1" attribute here and the link to Wikipedia entry in the Wikidate item, the "et al." disappears. | et_al = false | w1 = Androgen backdoor pathway --> | correspondence = | journal = WikiJournal of Medicine | license = | abstract = The term "backdoor pathway" is sometimes used to specify different androgen steroidogenic pathways that avoid testosterone as an intermediate product. Although the term was initially defined as a metabolic route by which the 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes towards potent androgens have been discovered, which are also described as backdoor pathways. Some of the routes lead to 11-oxygenated androgens that are clinically relevant agonists of the androgen receptor. This review aims to provide a clear, comprehensive description that includes all currently known metabolic routes. Patient comprehension and the clinical diagnosis of relevant conditions such as hyperandrogenism can be impaired by the lack of clear and consistent knowledge of alternative androgen pathways; the authors hope this review will accurately disseminate such knowledge to facilitate the beneficial treatment of such patients. | keywords = testosterone, 11-oxygenated androgen, 11-oxyandrogen, 11-ketotestosterone, hyperandrogenism }} ==Introduction== The classical view of androgen steroidogenesis involves the combination of adrenal and gonadal pathways that convert cholesterol to the androgen testosterone (T), which in turn converts to the potent androgen 5α-dihydrotestosterone (DHT). Broadly, androgens are understood to exert their primary effects through binding to cytosolic Androgen Receptor (AR) which is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via Androgen Responsive Elements.<ref name="pmid12089231">{{Cite journal|last=Gelmann|first=Edward P.|year=2022|title=Molecular Biology of the Androgen Receptor|url=https://ascopubs.org/doi/10.1200/JCO.2002.10.018|journal=Journal of Clinical Oncology|language=en|volume=20|issue=13|pages=3001–3015|doi=10.1200/JCO.2002.10.018|pmid=12089231 |issn=0732-183X}}</ref> In 2003, a metabolic route to DHT that did not proceed through T was discovered in the tammar wallaby.<ref name="pmid12538619">{{cite journal|last1=Wilson|first1=Jean D.|last2=Auchus|first2=Richard J.|last3=Leihy|first3=Michael W.|last4=Guryev|first4=Oleg L.|last5=Estabrook|first5=Ronald W.|last6=Osborn|first6=Susan M.|last7=Shaw|first7=Geoffrey|last8=Renfree|first8=Marilyn B.|title=5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate|journal=Endocrinology|year=2003 |volume=144|issue=2|pages=575–80|doi=10.1210/en.2002-220721|pmid=12538619|s2cid=84765868}}</ref> Shortly after this study, it was hypothesized that human steroidogenic enzymes are capable of catalyzing this pathway<ref name="pmid15519890">{{cite journal|last1=Auchus|first1=Richard J.|year=2004|title=The backdoor pathway to dihydrotestosterone|journal=Trends in Endocrinology and Metabolism: TEM|volume=15|issue=9|pages=432–8|doi=10.1016/j.tem.2004.09.004|pmid=15519890|s2cid=10631647}}</ref> and the potential clinical relevance in conditions involving androgen biosynthesis was proposed. Since then, steroidogenic androgen pathways to potent 11-oxygenated androgens have also been discovered and proposed as clinically relevant.<ref name="pmid27519632">{{cite journal |title=A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids |journal=Mol Cell Endocrinol |volume=441 |pages=76–85 |year=2017 |pmid=27519632 |doi=10.1016/j.mce.2016.08.014|last1=Pretorius |first1=Elzette |last2=Arlt |first2=Wiebke |last3=Storbeck |first3=Karl-Heinz |s2cid=4079662 |url=http://pure-oai.bham.ac.uk/ws/files/30346231/Pretorius_et_al_manuscript.pdf }}</ref><ref name="pmid32203405">{{cite journal |title=11-Oxygenated androgens in health and disease |journal=Nat Rev Endocrinol |volume=16 |issue=5 |pages=284–296 |year=2020 |pmid=32203405 |pmc=7881526 |doi=10.1038/s41574-020-0336-x|last1=Turcu |first1=Adina F. |last2=Rege |first2=Juilee |last3=Auchus |first3=Richard J. |last4=Rainey |first4=William E. }}</ref><ref name="pmid33539964">{{cite journal|last1=Barnard|first1=Lise|last2=du Toit|first2=Therina|last3=Swart|first3=Amanda C.|title=Back where it belongs: 11β-hydroxyandrostenedione compels the re-assessment of C11-oxy androgens in steroidogenesis|url=https://pubmed.ncbi.nlm.nih.gov/33539964|journal=Molecular and Cellular Endocrinology|year=2021 |volume=525|pages=111189|doi=10.1016/j.mce.2021.111189|issn=1872-8057|pmid=33539964|s2cid=231776716 }}</ref> The discovery of these "alternative androgen pathways" can confound the search for clinical information when androgen steroidogenesis is relevant. Studies across different androgen pathways have also, confusingly, used different names for the same metabolic intermediates. In addition, pathways in studies sometimes differ in the precise initial/terminal molecules and the inclusion/exclusion of such points can hinder queries in electronic pathway databases. Alternative androgen pathways are now known to be responsible for the production of biologically active androgens in humans, and there is growing evidence that they play a role in clinical conditions associated with hyperandrogenism. While naming inconsistencies are notoriously common when it comes to biomolecules,<ref name="pmid30736318">{{cite journal|last1=Pham|first1=Nhung|last2=van Heck|first2=Ruben G. A.|last3=van Dam|first3=Jesse C. J.|last4=Schaap|first4=Peter J.|last5=Saccenti|first5=Edoardo|last6=Suarez-Diez|first6=Maria|year=2019|title=Consistency, Inconsistency, and Ambiguity of Metabolite Names in Biochemical Databases Used for Genome-Scale Metabolic Modelling|journal=Metabolites|volume=9|issue=2|page=28|doi=10.3390/metabo9020028|issn=2218-1989|pmc=6409771|pmid=30736318|doi-access=free}}</ref> understanding androgen steroidogenesis at the level of detail presented in this paper and establishing consensus names and pathway specifications would facilitate access to information towards diagnosis and patient comprehension. ==History== === Backdoor Pathways to 5α-Dihydrotestosterone === In 1987, Eckstein et al. incubated rat testicular microsomes in presence of radiolabeled steroids and demonstrated that 5α-androstane-3α,17β-diol can be produced in immature rat testes from progesterone (P4), 17α-hydroxyprogesterone (17-OHP) and androstenedione (A4) but preferentially from 17-OHP.<ref name="pmid3828389">{{cite journal|last1=Eckstein|first1=B.|last2=Borut|first2=A.|last3=Cohen|first3=S.|title=Metabolic pathways for androstanediol formation in immature rat testis microsomes|journal=Biochimica et Biophysica Acta (BBA) - General Subjects |year=1987 |url=https://pubmed.ncbi.nlm.nih.gov/3828389|volume=924|issue=1|pages=1–6|doi=10.1016/0304-4165(87)90063-8|issn=0006-3002|pmid=3828389}}</ref> While "androstanediol" was used to denote both 5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol, we use "3α-diol" to abbreviate 5α-androstane-3α,17β-diol in this paper as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. Tammar wallaby pouch young do not show sexually dimorphic circulating levels of T and DHT during prostate development, which led Shaw et al. to hypothesize in 2000 that another pathway was responsible for AR activation in this species.<ref name="pmid11035809" /> While 3α-diol has a reduced AR binding affinity relative to DHT by 5 orders of magnitude and is generally described as AR inactive, it was known 3α-diol can be oxidized back to DHT via the action of a number of dehydrogenases.<ref name="pmid11514561">{{cite journal|last1=Nahoum|first1=Virginie|last2=Gangloff|first2=Anne|last3=Legrand|first3=Pierre|last4=Zhu|first4=Dao-Wei|last5=Cantin|first5=Line|last6=Zhorov|first6=Boris S.|last7=Luu-The|first7=Van|last8=Labrie|first8=Fernand|last9=Breton|first9=Rock|year=2001|title=Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution|journal=J Biol Chem|volume=276|issue=45|pages=42091–8|doi=10.1074/jbc.M105610200|pmid=11514561|doi-access=free|last10=Lin|first10=Sheng-Xiang}}</ref><ref name="pmid18923939">{{cite journal|last1=Dozmorov|first1=Mikhail G.|last2=Yang|first2=Qing|last3=Matwalli|first3=Adam|last4=Hurst|first4=Robert E.|last5=Culkin|first5=Daniel J.|last6=Kropp|first6=Bradley P.|last7=Lin|first7=Hsueh-Kung|year=2007|title=5alpha-androstane-3alpha,17beta-diol selectively activates the canonical PI3K/AKT pathway: a bioinformatics-based evidence for androgen-activated cytoplasmic signaling|journal=Genomic Med|volume=1|issue=3–4|pages=139–46|doi=10.1007/s11568-008-9018-9|pmc=2269037|pmid=18923939}}</ref><ref name="Nishiyama2011">{{cite journal|last1=Nishiyama|first1=Tsutomu|last2=Ishizaki|first2=Fumio|last3=Takizawa|first3=Itsuhiro|last4=Yamana|first4=Kazutoshi|last5=Hara|first5=Noboru|last6=Takahashi|first6=Kota|year=2011|title=5α-Androstane-3α 17β-diol Will Be a Potential Precursor of the Most Active Androgen 5α-Dihydrotestosterone in Prostate Cancer|journal=Journal of Urology|volume=185|issue=4S|doi=10.1016/j.juro.2011.02.378}}</ref><ref name="pmid9183566">{{Cite journal|last=Penning|first=Trevor M.|year=1997|title=Molecular Endocrinology of Hydroxysteroid Dehydrogenases| url=https://academic.oup.com/edrv/article/18/3/281/2530742|journal=Endocrine Reviews|language=en|volume=18|issue=3|pages=281–305|doi=10.1210/edrv.18.3.0302|pmid=9183566 |s2cid=29607473 |issn=0163-769X}}</ref> Shaw et al. showed that prostate formation in these wallaby is caused by circulating 3α-diol (generated in the testes) and led to their prediction that 3α-diol acts in target tissues via conversion to DHT.<ref name="pmid11035809">{{cite journal|last1=Shaw|first1=G.|last2=Renfree|first2=M. B.|last3=Leihy|first3=M. W.|last4=Shackleton|first4=C. H.|last5=Roitman|first5=E.|last6=Wilson|first6=J. D.|year=2000|title=Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=97|issue=22|pages=12256–12259|bibcode=2000PNAS...9712256S|doi=10.1073/pnas.220412297|issn=0027-8424|pmc=17328|pmid=11035809|doi-access=free}}</ref> In 2003, Wilson et al. incubated the testes of tammar wallaby pouch young with radiolabeled progesterone to show that 5α reductase expression in this tissue enabled a novel pathway from 17-OHP to 3α-diol without T as an intermediate:<ref name="pmid12538619" />{{unbulleted list|<small>17α-hydroxyprogesterone (17OHP) → 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The authors hypothesized that a high level of 5α-reductase in the virilizing wallaby testes causes most C₁₉ steroids to be 5α-reduced to become ready DHT precursors. In 2004, Mahendroo et al. demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby:<ref name="pmid15249131">{{cite journal|last1=Mahendroo|first1=Mala|last2=Wilson|first2=Jean D.|last3=Richardson|first3=James A.|last4=Auchus|first4=Richard J.|year=2004|title=Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways|url=https://pubmed.ncbi.nlm.nih.gov/15249131|journal=Molecular and Cellular Endocrinology|volume=222|issue=1–2|pages=113–120|doi=10.1016/j.mce.2004.04.009|issn=0303-7207|pmid=15249131|s2cid=54297812}}</ref>{{unbulleted list|<small>progesterone (P4) → 5α-dihydroprogesterone (5α-DHP) → 5α-pregnan-3α-ol-20-one (AlloP5)→ 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol)</small>}}The term "backdoor pathway" was coined by Auchus in 2004<ref name="pmid15519890" /> where it was defined as a route to DHT that: (1) bypasses conventional intermediates A4 and T; (2) involves 5α-reduction of the 21-carbon precursors (pregnanes) to 19-carbon products (androstanes) and (3) involves the 3α-oxidation of 3α-diol to DHT. This alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions in humans when the canonical androgen biosynthetic pathway cannot fully explain the observed consequences. The pathway was described as:{{unbulleted list|<small>17α-hydroxyprogesterone (17-OHP) → 17-OH-DHP (5α-pregnan-17α-ol-3,20-dione) → 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) → 5α-androstan-3α-ol-17-one (AST) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT)</small>}}The clinical relevance of these results was demonstrated in 2012 for the first time when Kamrath et al. attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (CYP21A2) deficiency.<ref name="pmid22170725" /> === 5α-Dione Pathway === In 2011, Chang et al. demonstrated that an alternative pathway to DHT was dominant and possibly essential in castration-resistant prostate cancer (CRPC) by presenting evidence from cell culture and xenograft models:<ref name="pmid21795608" />{{unbulleted list|<small>androstenedione (A4) → androstanedione (5α-dione) → 5α-dihydrotestosterone (DHT)</small>}}While this pathway was described as the "5α-dione pathway" in a 2012 review,<ref name="pmid22064602">{{cite journal |title=The 5α-androstanedione pathway to dihydrotestosterone in castration-resistant prostate cancer |journal=J Investig Med |volume=60 |issue=2 |pages=504–7 |year=2012 |pmid=22064602 |pmc=3262939 |doi=10.2310/JIM.0b013e31823874a4 |last1=Sharifi |first1=Nima }}</ref> the existence of such a pathway in the prostate was hypothesized in a 2008 review by Luu-The et al.<ref name="pmid18471780" /> A modern outlook of the synthesis of the backdoor pathways to DHT and the 5α-dione pathway is shown in Figure 2. === 11-Oxygenated Androgen Pathways === 11-Oxygenated androgens are the products of another alternative androgen pathway found in humans. The most potent 11-oxo androgens are 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT).<ref name="pmid23856005" /> 11-Oxygenated androgens were known since the 1950s to be products of the human adrenal, but their role as substrates to potent androgens had been overlooked in humans though they were known to be the main androgens in teleost fishes.<ref name="pmid30959151">{{cite journal |title=Circulating 11-oxygenated androgens across species |journal=J Steroid Biochem Mol Biol |volume=190 |pages=242–249 |year=2019 |pmid=30959151 |pmc=6733521 |doi=10.1016/j.jsbmb.2019.04.005|last1=Rege |first1=Juilee |last2=Garber |first2=Scott |last3=Conley |first3=Alan J. |last4=Elsey |first4=Ruth M. |last5=Turcu |first5=Adina F. |last6=Auchus |first6=Richard J. |last7=Rainey |first7=William E. }}</ref><ref name="pmid27519632" /><ref name="pmid34171490" /><ref name="pmid23386646" /> Rege et al. in 2013 measured 11-oxygenated androgens in healthy women and showed the 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) activation of human AR.<ref name="pmid23386646" /> In 2013, Storbeck et al. demonstrated the existence of 11-oxygenated androgen pathways in androgen-dependent prostate cancer cell culture.<ref name="pmid23856005">{{cite journal|title=11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer? |journal=Mol Cell Endocrinol |volume=377 |issue=1–2 |pages=135–46 |pmid=23856005 |doi=10.1016/j.mce.2013.07.006 |s2cid=11740484 |last1=Storbeck |first1=Karl-Heinz |last2=Bloem |first2=Liezl M. |last3=Africander |first3=Donita |last4=Schloms |first4=Lindie |last5=Swart |first5=Pieter |last6=Swart |first6=Amanda C. |year=2013 }}</ref> The authors indicated that A4 is converted 1β-hydroxyandrostenedione (11OHA4) which can ultimately be converted into 11KT and 11KDHT as shown in Figure 4. The authors found that 11KT activity is comparable to that of T, and 11-ketodihydrotestosterone (11KDHT) activity is comparable to that of DHT, while the activities of 11OHT and 5α-dihydro-11β-hydroxytestosterone (11OHDHT) were observed to be about half of T and DHT, respectively. However, androgen activity in that study was only assessed at a single concentration of 1 nM.<ref name="pmid23856005" /> To confirm androgen activity of 11KT and 11KDHT, a study by Pretorius et al. performing full dose responses showed in 2016 that 11KT and 11KDHT both bind and activate the human AR with affinities, potencies, and efficacies that are similar to that of T and DHT, respectively.<ref name="pmid27442248">{{cite journal|last1=Pretorius|first1=Elzette|last2=Africander|first2=Donita J.|last3=Vlok|first3=Maré|last4=Perkins|first4=Meghan S.|last5=Quanson|first5=Jonathan|last6=Storbeck|first6=Karl-Heinz|year=2016|title=11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored|journal=PLOS ONE|volume=11|issue=7|pages=e0159867|doi=10.1371/journal.pone.0159867|pmc=4956299|pmid=27442248|doi-access=free}}</ref> These findings were later confirmed in 2021<ref name="pmid34990809">{{cite journal|last1=Handelsman|first1=David J.|last2=Cooper|first2=Elliot R.|last3=Heather|first3=Alison K.|year=2022|title=Bioactivity of 11 keto and hydroxy androgens in yeast and mammalian host cells|journal=J Steroid Biochem Mol Biol|volume=218|issue=|pages=106049|doi=10.1016/j.jsbmb.2021.106049|pmid=34990809|s2cid=245635429}}</ref> and 2022.<ref name="pmid35046557">{{cite journal|last1=Snaterse|first1=Gido|last2=Mies|first2=Rosinda|last3=Van Weerden|first3=Wytske M.|last4=French|first4=Pim J.|last5=Jonker|first5=Johan W.|last6=Houtsmuller|first6=Adriaan B.|last7=Van Royen|first7=Martin E.|last8=Visser|first8=Jenny A.|last9=Hofland|first9=Johannes|year=2022|title=Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids|url=https://pure.eur.nl/ws/files/48975803/s41391_022_00491_z.pdf|journal=Prostate Cancer Prostatic Dis|doi=10.1038/s41391-022-00491-z|pmid=35046557|s2cid=246040148}}</ref> Bloem et al. in 2015<ref name="pmid25869556">{{cite journal|last1=Bloem|first1=Liezl M.|last2=Storbeck|first2=Karl-Heinz|last3=Swart|first3=Pieter|last4=du Toit|first4=Therina|last5=Schloms|first5=Lindie|last6=Swart|first6=Amanda C.|year=2015|title=Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas|url=https://pubmed.ncbi.nlm.nih.gov/25869556|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=153|pages=80–92|doi=10.1016/j.jsbmb.2015.04.009|issn=1879-1220|pmid=25869556|s2cid=31332668}}</ref> demonstrated that androgen pathways towards those 11-keto and 11β-hydroxy androgens can bypass A4 and T to produce 11KDHT in pathways similar to a backdoor pathway to DHT. This similarity led to the description of pathways from P4 and 17OHP to 11-oxyandrogens as "backdoor" pathways,<ref name="pmid25869556" /> which was further characterized in subsequent studies as contributing to active and biologically relevant androgens.<ref name="pmid28774496">{{cite journal|last1=Barnard|first1=Lise|last2=Gent|first2=Rachelle|last3=Van Rooyen|first3=Desmaré|last4=Swart|first4=Amanda C.|year=2017|title=Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone|url=https://www.sciencedirect.com/science/article/abs/pii/S0960076017302091|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=174|pages=86–95|doi=10.1016/j.jsbmb.2017.07.034|pmid=28774496|s2cid=24071400}}</ref><ref name="pmid29277707">{{cite journal|last1=van Rooyen|first1=Desmaré|last2=Gent|first2=Rachelle|last3=Barnard|first3=Lise|last4=Swart|first4=Amanda C.|year=2018|title=The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=178|pages=203–212|doi=10.1016/j.jsbmb.2017.12.014|pmid=29277707|s2cid=3700135}}</ref><ref name="pmid32007561">{{cite journal|last1=Van Rooyen|first1=Desmaré|last2=Yadav|first2=Rahul|last3=Scott|first3=Emily E.|last4=Swart|first4=Amanda C.|year=2020|title=CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=199|pages=105614|doi=10.1016/j.jsbmb.2020.105614|pmid=32007561|s2cid=210955834}}</ref> A diagram of 11-oxygenated androgen steroidogenesis is shown in Figure 4. ==Definition== We suggest the term "alternative androgen pathway" to refer to any pathway that produces potent androgens without a T intermediate. This subsumes all three groups of androgen pathways described in the previous section. A new term that describes the three groups pathways (as well as future discoveries) will allow a single entry point into scientific information when alternatives to canonical<ref name="NBK557634">{{cite book|url=https://www.ncbi.nlm.nih.gov/books/NBK557634/|title=Biochemistry, Dihydrotestosterone|publisher=StatPearls|year=2022}}</ref><ref name="pmid30763313">{{cite journal|last1=O'Shaughnessy|first1=Peter J.|last2=Antignac|first2=Jean Philippe|last3=Le Bizec|first3=Bruno|last4=Morvan|first4=Marie-Line|last5=Svechnikov|first5=Konstantin|last6=Söder|first6=Olle|last7=Savchuk|first7=Iuliia|last8=Monteiro|first8=Ana|last9=Soffientini|first9=Ugo|year=2019|title=Alternative (backdoor) androgen production and masculinization in the human fetus|journal=PLOS Biology|volume=17|issue=2|pages=e3000002|doi=10.1371/journal.pbio.3000002|pmc=6375548|pmid=30763313|last10=Johnston|first10=Zoe C.|last11=Bellingham|first11=Michelle|last12=Hough|first12=Denise|last13=Walker|first13=Natasha|last14=Filis|first14=Panagiotis|last15=Fowler|first15=Paul A.|editor-last1=Rawlins|editor-first1=Emma}}</ref><ref name="pmid31900912" /> androgen pathway must be considered. ==Nomenclature and Background== Complex naming rules for organic chemistry lead to the use of incorrect steroid names in studies. The presence of incorrect names impairs the ability to query information about androgen pathways. Since we were able to find many examples of incorrect names for molecules referred to in this paper in Google Scholar searches<ref name="google-pregnan17diol" /><ref name="google-pregnane17ol" />, we have added this expository section on steroid nomenclature to facilitate the use of correct names. Almost all biologically relevant steroids can be presented as a derivative of a parent hydrocarbon structure. These parent structures have specific names, such as pregnane, androstane, etc. The derivatives carry various functional groups called suffixes or prefixes after the respective numbers indicating their position in the steroid nucleus.<ref name="pmid2606099-parent-elisions" /> The widely-used steroid names such as progesterone, testosterone or cortisol can also be used as base names to derive new names, however, by adding prefixes only rather than suffixes, e.g., the steroid 17α-hydroxyprogesterone has a hydroxy group (-OH) at position 17 of the steroid nucleus comparing to progesterone. The letters α and β<ref name="pmid2606099-rs">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |year=1989 |volume=186 |issue=3 |pages=431 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=431|chapter=3S-1.4|quote=3S-1.4. Orientation of projection formulae When the rings of a steroid are denoted as projections onto the plane of the paper, the formula is normally to be oriented as in 2a. An atom or group attached to a ring depicted as in the orientation 2a is termed α (alpha) if it lies below the plane of the paper or β (beta) if it lies above the plane of the paper. }}</ref> denote absolute stereochemistry at chiral centers (a specific nomenclature distinct from the R/S convention<ref name="norc-rs">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-91|pages=868|quote-page=868|quote=P-91.2.1.1 Cahn-Ingold-Prelog (CIP) stereodescriptors Some stereodescriptors described in the Cahn-Ingold-Prelog (CIP) priority system, called ‘CIP stereodescriptors’, are recommended to specify the configuration of organic compounds, as described and exemplified in this Chapter and applied in Chapters P-1 through P-8, and in the nomenclature of natural products in Chapter P-10. The following stereodescriptors are used as preferred stereodescriptors (see P-92.1.2): (a) ‘R’ and ‘S’, to designate the absolute configuration of tetracoordinate (quadriligant) chirality centers;}}</ref> of organic chemistry). In steroids drawn from the standard perspective used in this paper, α-bonds are depicted on figures as dashed wedges and β-bonds as wedges. The molecule "11-deoxycortisol" is an example of a derived name that uses cortisol as a parent structure without an oxygen atom (hence "deoxy") attached to position 11 (as a part of a hydroxy group).<ref name="norc-deoxy">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-13.8.1.1|pages=66|quote-page=66|quote=P-13.8.1.1 The prefix ‘de’ (not ‘des’), followed by the name of a group or atom (other than hydrogen), denotes removal (or loss) of that group and addition of the necessary hydrogen atoms, i.e., exchange of that group with hydrogen atoms. As an exception, ‘deoxy’, when applied to hydroxy compounds, denotes the removal of an oxygen atom from an –OH group with the reconnection of the hydrogen atom. ‘Deoxy’ is extensively used as a subtractive prefix in carbohydrate nomenclature (see P-102.5.3).}}</ref> The numbering of positions of carbon atoms in the steroid nucleus is set in a template found in the Nomenclature of Steroids<ref name="pmid2606099-numbering">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=430|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=3S-1.l. Numbering and ring letters Steroids are numbered and rings are lettered as in formula 1|quote-page=430}}</ref> that is used regardless of whether an atom is present in the steroid in question. Although the nomenclature defines more than 30 positions, we need just positions up to 21 for the steroids described here (see Figure 1). [[File:steroid-numbering-to-21-opt.svg|thumb|Numbering of carbon atoms up to position 21 (positions 18 and 19 are omitted) in a hypothetical steroid nucleus, as defined by the Nomenclature of Steroids]] Unsaturation (presence of double bonds between carbon atoms in the steroid nucleus) is indicated by changing -ane to -ene.<ref name="pmid2606099-unsaturation">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=436–437 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099 |quote-page=436-437|quote=3S-2.5 Unsaturation Unsaturation is indicated by changing -ane to -ene, -adiene, -yne etc., or -an- to -en-, -adien-, -yn- etc. Examples: Androst-5-ene, not 5-androstene 5α-Cholest-6-ene 5β-Cholesta-7,9(11)-diene 5α-Cholest-6-en-3β-ol Notes 1) It is now recommended that the locant of a double bond is always adjacent to the syllable designating the unsaturation. [...] 3) The use of Δ (Greek capital delta) character is not recommended to designate unsaturation in individual names. It may be used, however, in generic terms, like ‘Δ⁵-steroids’}}</ref> This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta), for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ⁴-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ⁴-androstene-3,11,17-trione). However, the Nomenclature of Steroids recommends the locant of a double bond to be always adjacent to the syllable designating the unsaturation, therefore, having it as a suffix rather than a prefix, and without the use of the Δ character, i.e. pregn-4-ene-11β,17α-diol-3,20-dione or androst-4-ene-3,11,17-trione. The double bond is designated by the lower-numbered carbon atom, i.e. "Δ⁴-" or "4-ene" means the double bond between positions 4 and 5. Saturation of double bonds (replacing a double bond between two carbon atoms with a single bond so that each of these atoms can attach one additional hydrogen atom) of a parent steroid can be done by adding "dihydro-" prefix,<ref name="norc">{{cite book|first1=Henri|last1=Favre|first2=Warren|last2=Powell|title=Nomenclature of Organic Chemistry - IUPAC Recommendations and Preferred Names 2013|publisher=The Royal Society of Chemistry|year=2014|isbn=978-0-85404-182-4|doi=10.1039/9781849733069|chapter=P-3|quote=P-31.2.2 General methodology ‘Hydro’ and ‘dehydro’ prefixes are associated with hydrogenation and dehydrogenation, respectively, of a double bond; thus, multiplying prefixes of even values, as ‘di’, ‘tetra’, etc. are used to indicate the saturation of double bond(s), for example ‘dihydro’, ‘tetrahydro’; or creation of double (or triple) bonds, as ‘didehydro’, etc. In names, they are placed immediately at the front of the name of the parent hydride and in front of any nondetachable prefixes. Indicated hydrogen atoms have priority over ‘hydro‘ prefixes for low locants. If indicated hydrogen atoms are present in a name, the ‘hydro‘ prefixes precede them.}}</ref> i.e. saturation of a double bond between positions 4 and 5 of testosterone with two hydrogen atoms may yield 4,5α-dihydrotestosterone or 4,5β-dihydrotestosterone. Generally, when there is no ambiguity, one number of a hydrogen position from a steroid with a saturated bond may be omitted, leaving only the position of the second hydrogen atom, e.g., 5α-dihydrotestosterone or 5β-dihydrotestosterone. Some steroids are traditionally grouped as Δ⁵-steroids (with a double bond between carbons 5 and 6 junctions (Figure 1)) and some as Δ⁴ steroids (with a double bond between carbons 4 and 5), respectively.<ref name="pmid21051590">{{cite journal |title=The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders |journal=Endocr Rev |volume=32 |issue=1 |pages=81–151 |pmid=21051590 |pmc=3365799 |doi=10.1210/er.2010-0013|last1=Miller |first1=Walter L. |last2=Auchus |first2=Richard J.|year=2011 }}</ref><ref name="pmid2606099-unsaturation"/> Canonical androgen synthesis is generally described as having a Δ⁵ pathway (from cholesterol to pregnenolone (P5) to 17α-hydroxypregnenolone (17OHP5) to DHEA to androstenediol (A5)) and of the Δ⁴ pathway (from P4 to 17-OHP to A4 to T). The abbreviations like "P4" and "A4" are used for convenience to designate them as Δ⁴-steroids, while "P5" and "A5" - as Δ⁵-steroids, respectively. The suffix -ol denotes a hydroxy group, while the suffix -one denotes an oxo group. When two or three identical groups are attached to the base structure at different positions, the suffix is ​​indicated as -diol or -triol for hydroxy, and -dione or -trione for oxo groups, respectively. For example, 5α-pregnane-3α,17α-diol-20-one has a hydrogen atom at the 5α position (hence the "5α-" prefix), two hydroxy groups (-OH) at the 3α and 17α positions (hence "3α,17α-diol" suffix) and an oxo group (=O) at the position 20 (hence the "20-one" suffix). However, erroneous use of suffixes can be found, e.g., "5α-pregnan-17α-diol-3,11,20-trione"<ref name="google-pregnan17diol">{{cite web | url=https://scholar.google.com/scholar?&q=%225%CE%B1-pregnan-17%CE%B1-diol-3%2C11%2C20-trione%22| title=Google Scholar search results for "5α-pregnan-17α-diol-3,11,20-trione" that is an incorrect name| year=2022}}</ref> [''sic''] — since it has just one hydroxy group (at 17α) rather than two, then the suffix should be -ol, rather than -diol, so that the correct name to be "5α-pregnan-17α-ol-3,11,20-trione". According to the rule set in the Nomenclature of Steroids, the terminal "e" in the parent structure name should be elided before the vowel (the presence or absence of a number does not affect such elision).<ref name="pmid2606099-parent-elisions">{{cite journal |title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989 |journal=Eur J Biochem |volume=186 |issue=3 |pages=441 |doi=10.1111/j.1432-1033.1989.tb15228.x |pmid=2606099|quote-page=441|quote=3S-4. FUNCTIONAL GROUPS 3S-4.0. General Nearly all biologically important steroids are derivatives of the parent hydrocarbons (cf. Table 1) carrying various functional groups. [...] Suffixes are added to the name of the saturated or unsaturated parent system (see 33-2.5), the terminal e of -ane, -ene, -yne, -adiene etc. being elided before a vowel (presence or absence of numerals has no effect on such elisions).}}</ref> This means, for instance, that if the suffix immediately appended to the parent structure name begins with a vowel, the trailing "e" is removed from that name. An example of such removal is "5α-pregnan-17α-ol-3,20-dione", where the last "e" of "pregnane" is dropped due to the vowel ("o") at the beginning of the suffix -ol. Some authors incorrectly use this rule, eliding the terminal "e" where it should be kept, or vice versa.<ref name="google-pregnane17ol">{{cite web | url=https://scholar.google.com/scholar?q=%225%CE%B1-pregnane-17%CE%B1-ol-3%2C20-dione%22| title=Google Scholar search results for "5α-pregnane-17α-ol-3,20-dione" that is an incorrect name| year=2022}}</ref> In the term "11-oxygenated" applied to a steroid, "oxygenated" refers to the presence of the oxygen atom in a group; this term is consistently used within the chemistry of the steroids<ref name="chemster">{{cite journal|last1=Makin|first1=H.L.J.|last2=Trafford|first2=D.J.H.|year=1972|title=The chemistry of the steroids|journal=Clinics in Endocrinology and Metabolism|volume=1|issue=2|pages=333–360|doi=10.1016/S0300-595X(72)80024-0}}</ref> since as early as 1950s.<ref name="pmid13167092">{{cite journal|last1=Bongiovanni|first1=A. M.|last2=Clayton|first2=G. W.|year=1954|title=Simplified method for estimation of 11-oxygenated neutral 17-ketosteroids in urine of individuals with adrenocortical hyperplasia|url=|journal=Proc Soc Exp Biol Med|volume=85|issue=3|pages=428–9|doi=10.3181/00379727-85-20905|pmid=13167092|s2cid=8408420}}</ref><ref name="pmid23386646" /> Some studies use the term "11-oxyandrogens"<ref name="11oxyhs">{{cite journal|last1=Slaunwhite|first1=W.Roy|last2=Neely|first2=Lavalle|last3=Sandberg|first3=Avery A.|year=1964|title=The metabolism of 11-Oxyandrogens in human subjects|journal=Steroids|volume=3|issue=4|pages=391–416|doi=10.1016/0039-128X(64)90003-0}}</ref><ref name="pmid29277706" /><ref name="pmid35611324" /> potentially as an abbreviation for 11-oxygenated androgens, to emphasize that they all have an oxygen atom attached to carbon at position 11.<ref name="pmid32203405" /> However, in chemical nomenclature, the prefix "oxy" refers to an ether, i.e., a compound with an oxygen atom connected to two alkyl or aryl groups (-O-), therefore, using the part "oxy" for a steroid may be misleading. The oxo group (=O) bound to a carbon atom at position 11 forms a larger, ketone group (R₂C=O), hence the prefix "11-keto" used in the medical literature. However, the 1989 recommendations of the Joint Commission on Biochemical Nomenclature discourage the application of the term "11-keto" for steroids, and favor the term "11-oxo", because keto denotes "R₂C=O", while only "=O" is attached to the carbon at position 11, rather than a group with an additional carbon atom, therefore, the same carbon atom should not be specified twice.<ref name="pmid2606099-keto">{{cite journal|year=1989|title=IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). The nomenclature of steroids. Recommendations 1989|journal=Eur J Biochem|volume=186|issue=3|pages=429–58|doi=10.1111/j.1432-1033.1989.tb15228.x|pmid=2606099|quote=The prefix oxo- should also be used in connection with generic terms, e.g., 17-oxo steroids. The term ‘17-keto steroids’, often used in the medical literature, is incorrect because C-17 is specified twice, as the term keto denotes C=O|quote-page=430}}</ref> == Biochemistry == A more detailed description of each alternative androgen pathway described in the History section is provided below. Protein names are abbreviated by the standard gene names that they are encoded by (e.g., 5α-reductases type 1 is abbreviated by SRD5A1). Full enzyme names can be found in the Abbreviations section. === Backdoor Pathways to 5α-Dihydrotestosterone === While 5α-reduction is the last transformation in canonical androgen steroidogenesis, it is the first step in the backdoor pathways to 5α-dihydrotestosterone that acts on either 17-OHP or P4 which are ultimately converted to DHT.[[File:Androgen backdoor pathway.svg|thumb|left|The androgen backdoor pathways from 17α-hydroxyprogesterone or progesterone towards 5α-dihydrotestosterone roundabout testosterone and androstenedione (red arrows), as well as the "5α-dione" pathway that starts with 5α-reduction of androstenedione, embedded within canonical steroidogenesis (black arrows). Genes corresponding to the enzymes for catalysis are shown in boxed text with the associated arrow. Some additional proteins that are required for specific transformations (such as Steroidogenic acute regulatory protein (STAR), Cytochromes b₅, Cytochrome P450 reductase (POR)) are not shown for clarity.]] ====17α-Hydroxyprogesterone Pathway ==== [[File:Androgen backdoor pathway from 17-OHP to DHT.svg|thumb|right|The steroids involved in the metabolic pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone with roundabout of testosterone. The red circle indicates the change in molecular structure compared to the precursor.]] The first step of this pathway is the conversion of 17-OHP to 5α-pregnan-17α-ol-3,20-dione (17-OH-DHP, since it is also known as 17α-hydroxy-dihydroprogesterone). The reaction is catalyzed by SRD5A1.<ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> 17-OH-DHP is then converted to 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2 and AKR1C4)<ref name="pmid30763313" /><ref name="pmid21802064">{{cite journal|last1=Flück|first1=Christa E.|last2=Meyer-Böni|first2=Monika|last3=Pandey|first3=Amit V.|last4=Kempná|first4=Petra|last5=Miller|first5=Walter L.|last6=Schoenle|first6=Eugen J.|last7=Biason-Lauber|first7=Anna|year=2011|title=Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation|journal=American Journal of Human Genetics|volume=89|issue=2|pages=201–218|doi=10.1016/j.ajhg.2011.06.009|issn=1537-6605|pmc=3155178|pmid=21802064}}</ref> or 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), that also has 3α-reduction activity.<ref name="pmid9188497">{{cite journal |title=Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate |journal=J Biol Chem |volume=272 |issue=25 |pages=15959–66 |pmid=9188497 |doi=10.1074/jbc.272.25.15959|doi-access=free |last1=Biswas |first1=Michael G. |last2=Russell |first2=David W. |year=1997 }}</ref><ref name="pmid22114194">{{cite journal|title=Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer |journal=Proc Natl Acad Sci U S A |volume=108 |issue=50 |pages=20090–4 |pmid=22114194 |pmc=3250130 |doi=10.1073/pnas.1117772108|doi-access=free |last1=Muthusamy |first1=Selvaraj |last2=Andersson |first2=Stefan |last3=Kim |first3=Hyun-Jin |last4=Butler |first4=Ryan |last5=Waage |first5=Linda |last6=Bergerheim |first6=Ulf |last7=Gustafsson |first7=Jan-Åke |year=2011 |bibcode=2011PNAS..10820090M }}</ref> 5α-Pdiol is also known as 17α-hydroxyallopregnanolone or 17-OH-allopregnanolone. 5α-Pdiol is then converted to 5α-androstan-3α-ol-17-one (AST) by 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to C₁₉ steroid (an androstane or androgen). AST, in its turn, is 17β-reduced to 5α-androstane-3α,17β-diol (3α-diol) by 17β-hydroxysteroid dehydrogenase type 3 or type 5 (HSD17B3 and AKR1C3).<ref name="pmid31900912" /> The final step is 3α-oxidation of 3α-diol in target tissues to DHT by several 3α-oxidoreductases (HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9). This oxidation is not required in the canonical pathway. The pathway can be summarized as:{{unbulleted list|17-OHP → 17-OH-DHP → 5α-Pdiol → AST → 3α-diol → DHT}} ====Progesterone Pathway==== The pathway from P4 to DHT is similar to that described above from 17-OHP to DHT, but the initial substrate for 5α-reductase here is P4 rather than 17-OHP. In male fetuses, placental P4 acts as a substrate during the biosynthesis of backdoor androgens, which occur in multiple tissues. Enzymes related to this backdoor pathway in the human male fetus are mainly expressed in non-gonadal tissues, and the steroids involved in this pathway are also primarily present in non-gonadal tissues.<ref name="pmid30763313"/> The first step in this pathway is 5α-reduction of P4 towards 5α-dihydroprogesterone (5α-DHP) by SRD5A1. 5α-DHP is then converted to 5α-pregnan-3α-ol-20-one (AlloP5) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). AlloP5 is then converted to 5α-Pdiol by the 17α-hydroxylase activity of CYP17A1. This metabolic pathway proceeds analogously to DHT as the 17α-Hydroxyprogesterone Pathway. The pathway can be summarized as:{{unbulleted list|P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT}} === 5α-Dione Pathway === 5α-reduction is also the initial transformation of the 5α-dione pathway where A4 is converted to androstanedione (5α-dione) by SRDA51 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer.<ref name="pmid21795608"/> The 5α-dione can also transformed into AST, which can then be transformed into DHT along the common part of the backdoor pathways to DHT.<ref name="pmid18923939"/><ref name="Nishiyama2011"/><ref name="pmid9183566"/> This pathway can be summarized as:{{unbulleted list|A4 → 5α-dione → DHT<ref name="pmid21795608"/>}} === 11-Oxygenated Androgen Pathways === [[File:Routes to 11-oxyandrogens.svg|thumb|Routes to 11-oxygenated androgens in humans|thumb|left|Abbreviated routes to 11-oxygenated androgens with transformations annotated with gene names of corresponding enzymes. Certain CYP17A1 mediated reactions that transform 11-oxygenated androgens classes (grey box) are omitted for clarity. Δ⁵ compounds that are transformed to Δ⁴ compounds are also omitted for clarity.]] Routes leading to the production of the potent 11-oxygenated androgens<ref name="pmid27442248" /><ref name="pmid32203405" /><ref name="pmid30825506" /><ref name="pmid25869556" /> also fall under our definition of the alternative androgen pathways. As noted earlier, 11KT and 11DHT are the most potent members of this class while 11-oxygenated derivatives of A4, i.e. 11OHA4 and 11-ketoandrostenedione (11KA4, also known as adrenosterone), are not considered as active androgens.<ref name="pmid34990809" /><ref name="pmid35046557" /><ref name="pmid30825506">{{cite journal |title=The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with HSD11B2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis |journal=J Steroid Biochem Mol Biol |volume=189 |issue= |pages=116–126 |pmid=30825506 |doi=10.1016/j.jsbmb.2019.02.013|last1=Gent |first1=R. |last2=Du Toit |first2=T. |last3=Bloem |first3=L. M. |last4=Swart |first4=A. C. |year=2019 |s2cid=73490363 }}</ref> While this class of androgen does not ''require'' T or DHT as intermediate products in their synthesis, T ''may'' serve as a precursor for 11-oxygenated androgens. The first step in all routes to 11-oxygenated androgens is the 11β-hydroxylation of a steroid precursor.<ref name="pmid23685396" /><ref name="Haru1980" /><ref name="pmid22101210">{{cite journal |title=The influence of Aspalathus linearis (Rooibos) and dihydrochalcones on adrenal steroidogenesis: quantification of steroid intermediates and end products in H295R cells |journal=J Steroid Biochem Mol Biol |year=2012 |volume=128 |issue=3–5 |pages=128–38 |pmid=22101210 |doi=10.1016/j.jsbmb.2011.11.003|last1=Schloms |first1=Lindie |last2=Storbeck |first2=Karl-Heinz |last3=Swart |first3=Pieter |last4=Gelderblom |first4=Wentzel C.A. |last5=Swart |first5=Amanda C. |s2cid=26099234 }}</ref> The main route is the one that starts with 11β-hydroxylation of A4, with a minor contribution from the 11β-hydroxylation of T; the other routes that start from 11β-hydroxylation of pregnanes (P4 or 17-OHP) are only believed to occur under specific conditions such as CYP21A2 deficiency.<ref name="pmid33539964"/> Humans have two isozymes with 11β-hydroxylase activity, encoded by the genes ''CYP11B1'' (regulated by the adrenocorticotropic hormone, ACTH) and ''CYP11B2'' (regulated by angiotensin II).<ref name="pmid22217826">{{cite journal|title=Molecular biology of 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase enzymes |journal=J Steroid Biochem Mol Biol |volume=43 |issue=8 |pages=827–35 |pmid=22217826 |doi=10.1016/0960-0760(92)90309-7 |s2cid=19379671 |last1=White |first1=Perrin C. |last2=Pascoe |first2=Leigh |last3=Curnow |first3=Kathleen M. |last4=Tannin |first4=Grace |last5=Rösler |first5=Ariel |year=1992 }}</ref> The two isozymes in the adrenal glad catalyse the production 11OHA4 from A4<ref name="Haru1980">{{cite journal | last1=Haru | first1=Shibusawa | last2=Yumiko | first2=Sano | last3=Shoichi | first3=Okinaga | last4=Kiyoshi | first4=Arai | title=Studies on 11β-hydroxylase of the human fetal adrenal gland | journal=Journal of Steroid Biochemistry | publisher=Elsevier BV | volume=13 | issue=8 | year=1980 | issn=0022-4731 | doi=10.1016/0022-4731(80)90161-2 | pages=881–887| pmid=6970302 }}</ref><ref name="pmid22101210" /><ref name="pmid23685396" /> and 11β-hydroxytestosterone (11OHT) from T.<ref name="pmid23685396" /> These isozymes also catalyse the production of 11-oxygenated pregnanes: 4-pregnen-11β-ol-3,20-dione (11OHP4, also known as 21-deoxycorticosterone and 11β-hydroxyprogesterone)<ref name="pmid29277707" /> and 4-pregnene-11β,17α-diol-3,20-dione (21dF, since it is also known as 11β,17α-dihydroxyprogesterone and 21-deoxycortisol).<ref name="pmid28774496" /> Besides CYP11B1 and CYP11B2, additional enzymes are required for the synthesis of 11-oxygenated androgens. HSD11B2 converts 11β-hydroxy steroids to 11-oxo steroids (e.g., 11OHT to 11KT)<ref name="pmid23685396" /><ref name="pmid30825506" /> and AKR1C3 catalyses the conversion of 11KA4 to 11KT.<ref name="pmid29936123">{{cite journal |title=11-Oxygenated androgen precursors are the preferred substrates for aldo-keto reductase 1C3 (AKR1C3): Implications for castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=183 |issue= |pages=192–201 |year=2018 |pmid=29936123 |pmc=6283102 |doi=10.1016/j.jsbmb.2018.06.013|last1=Barnard |first1=Monique |last2=Quanson |first2=Jonathan L. |last3=Mostaghel |first3=Elahe |last4=Pretorius |first4=Elzette |last5=Snoep |first5=Jacky L. |last6=Storbeck |first6=Karl-Heinz }}</ref><ref name="pmid33444228" /><ref name="pmid35560164">{{cite journal |title=Conversion of Classical and 11-Oxygenated Androgens by Insulin-Induced AKR1C3 in a Model of Human PCOS Adipocytes |journal=Endocrinology |volume=163 |issue=7 |year=2022 |pmid=35560164 |doi=10.1210/endocr/bqac068 |last1=Paulukinas |first1=Ryan D. |last2=Mesaros |first2=Clementina A. |last3=Penning |first3=Trevor M. |s2cid=248776966 }}</ref> The production of 11KA4 and 11KT takes place in the periphery and the a lesser extent in the adrenal gland. These 11-oxygenated androgens may be converted by 5α-reductase which catalyses the production of 5α-androstane-3,11,17-trione (11K-5αdione) and 11KDHT following a pathway similar to that of the canonical androgen steroidogenesis pathway.<ref name="pmid23685396" /><ref name="pmid23856005" /><ref name="pmid25542845">{{cite journal |title=11β-Hydroxyandrostenedione: Downstream metabolism by 11βHSD, 17βHSD and SRD5A produces novel substrates in familiar pathways |journal=Mol Cell Endocrinol |volume=408 |issue= |pages=114–23 |pmid=25542845 |doi=10.1016/j.mce.2014.12.009|last1=Swart |first1=Amanda C. |last2=Storbeck |first2=Karl-Heinz |year=2015 |s2cid=23860408 }}</ref> ==== From Androstenedione or Testosterone Towards 11-Oxygenated Androgens ==== The predominant route in normal conditions consists of conversion of A4 to 11OHA4, then to 11KA4, and then to 11KT:<ref name="pmid23386646"/><ref name="pmid29936123"/><ref name="pmid33444228"/><ref name="pmid35560164"/> The initial 11β-hydroxylation of A4 and T to (respectively) 11OHA4 and 11β-hydroxytestosterone (11OHT) via CYP11B1 and CYP11B2. 11OHA4 and 11OHT can then be converted (via HSD11B2) to their 11-oxo forms, 4-androstene-3,11,17-trione (11KA4, since it is also known as 11-ketoandrostenedione) and 4-androsten-17β-ol-3,11-dione (11KT, since it is also known as 11-ketotestosterone). These four 11-oxygenated androgens, 11OHA4, 11OHT 11KA4, and 11KT can be ultimately converted to 11KDHT following the same metabolic route of A4 and T, however, it may be that 11KT is the primary active 11-oxygenated androgen, rather then 11KDHT: at least in prostate cancer 11KDHT has been found to circulate at substantially lower levels than DHT.<ref name="pmid30472582">{{cite journal |title=Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue |journal=J Pharm Biomed Anal |volume=164 |issue= |pages=642–652 |year=2019 |pmid=30472582 |doi=10.1016/j.jpba.2018.11.035 |last1=Häkkinen |first1=Merja R. |last2=Murtola |first2=Teemu |last3=Voutilainen |first3=Raimo |last4=Poutanen |first4=Matti |last5=Linnanen |first5=Tero |last6=Koskivuori |first6=Johanna |last7=Lakka |first7=Timo |last8=Jääskeläinen |first8=Jarmo |last9=Auriola |first9=Seppo |s2cid=53729550 }}</ref> HSD11B1 can catalyze the reverse reaction of 11-oxo androgens back to the 11-hydroxy androgens.<ref name="pmid23856005" /> Each of 11OHA4, 11KA4, 11OHT and 11KT can be reduced (via SRD5A1 and SRD5A2) 5α-androstan-11β-ol-3,17-dione (11OH-5αdione), 5α-androstane-3,11,17-trione (11K-5αdione), 5α-androstane-11β,17β-diol-3-one (11OHDHT, since it is also known as 11β-hydroxydihydrotestosterone) and 11KDHT, respectively. 11OH-5αdione, 11K-5αdione, 11OHDHT and 11KDHT can be converted to the inactive forms of these 11-oxygenated androgens, 5α-androstane-3α,11β-diol-17-one (11OHAST, since it also known as 11β-hydroxyandrosterone), 5α-androstan-3α-ol-11,17-dione (11KAST, since it is also known as 11-ketoandrosterone), 5α-androstane-3α,11β,17β-triol (11OH-3αdiol) and 5α-androstane-3α,17β-diol-11-one (11K-3αdiol) via 3α-reduction by AKR1C2 and AKR1C4. These 11-oxygenated androgens are also converted by HSD17B3, AKR1C3 and by HSD17B2. The steroids 11KA4, 11K-5αdione and 11KAST can be converted to 11KT, 11KDHT and 11K-3αdiol, respectively by HSD17B3 and AKR1C3. Given that the adrenal produces significantly more 11OHA4 than 11OHT<ref name="pmid23386646" /> it is much more likely that the majority of 11KT is produced as follows: 11OHA4 is converted to 11KA4 by HSD11B2; 11KA4 is then converted to 11KT by AKR1C3.<ref name="pmid23386646" /><ref name="pmid29936123" /> 11OHA4, 11OHAST and 11OH-5αdione are not converted to 11OHT, 11OHDHT or 11OH-3αdiol as these 11-hydroxy androgens and not substrates for HSD17B3 or AKR1C3. However, HSD17B2 converts 11OHT and 11OHDHT to 11OHA4 and 11OH-5αdione, respectively. HSD17B2 also converts 11KT, 11KDHT and 11K-3αdiol back to 11KA4, 11K-5αdione and 11KAST. To be specific, given that 11OHA4 is not a substrate for AKR1C3<ref name="pmid29936123" />, it requires the conversion to 11KA4 by HSD11B2 before it can be further converted to potent androgens such as 11KT. These complex pathways leading to the production of 11KT, 11KDHT and 11OHDHT from 11OHA4 and 11OHT set out above have been previously described in a 2021 review by Barnard et al.<ref name="pmid33539964"/> based on earlier ''in vitro'' studies.<ref name="pmid23856005" /><ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid29936123" /> The reactions mentioned above can be outlined as shown in Figure 4. ==== From Progesterone and 17α-Hydroxyprogesterone Towards 11-Oxygenated Androgens ==== The 11β-hydroxylation of P4 yields 11β-hydroxyprogesterone (11OHP4, also known as 21-deoxycorticosterone)<ref name="pmid29277707"/>, and that of 17-OHP converted to 21-deoxycortisol (21dF)<ref name="pmid28774496"/> — in both cases, by CYP11B1 and CYP11B2 respectively. The 11-hydroxylated pregnanes, 11OHP4 and 21dF, catalysed by the CYP11B isozymes also require HSD11B2 in the production of the 11-oxo forms: 4-pregnene-3,11,20-trione (also known as 11-ketoprogesterone (11KP4)) and 4-pregnen-17α-ol-3,11,20-trione (also known as 21-deoxycortisone (21dE)), respectively.<ref name="pmid28774496"/><ref name="pmid29277707"/><ref name="pmid32007561"/><ref name="pmid30825506"/> These four 11-oxygenated pregnanes, 11OHP4, 21dF, 11KP4 and 21dE are ultimately converted to 11KDHT following the same metabolic route of 17-OHP, consisting of five steps: The first step of this route is the conversion of 11OHP4, 11KP4, 21dF and 21dE by SRD5A1 and SRD5A2 to 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone (11OHDHP4), 5α-pregnane-3,11,20-trione (11KDHP4, since it is also known as 11-ketodihydroprogesterone), 5α-pregnane-11β,17α-diol-3,20-dione (11OHPdione) and 5α-pregnan-17α-ol-3,11,20-trione (11KPdione). 11OHDHP4, 11KDHP4, 11OHPdione and 11KPdione are then converted to 5α-pregnane-3α,11β-diol-20-one (3,11diOH-DHP4), 5α-pregnan-3α-ol-11,20-dione known as alfaxalone (ALF), 5α-pregnane-3α,11β,17α-triol-20-one (11OHPdiol) and 5α-pregnane-3α,17α-diol-11,20-dione (11KPdiol) via 3α-reduction by a 3α-hydroxysteroid dehydrogenase isozyme (AKR1C2/AKR1C4). 3,11diOH-DHP4, ALF, 11OHPdiol and 11KPdiol are then converted to 5α-androstane-3α,11β-diol-17-one (11OHAST) and 5α-androstane-3α-ol-11,17-dione (11KAST) by CYP17A1. In these reactions 11OHPdiol and 11KPdiol are converted to C₁₉ steroids by the 17,20-lyase activity of CYP17A1 which cleaves a side-chain (C17-C20 bond) from the steroid nucleus, converting a C₂₁ steroid (a pregnane) to a C₁₉ steroid (androgen). In the conversion of 3,11diOH-DHP4 and ALF to androgens, these steroids first undergo the hydroxylase activity and then the 17,20-lyase activity of CYP17A1.<ref name="pmid32007561" /> 11OHAST is first converted to 11KAST by HSD11B2 since is not a substrate for HSD11B3 or HSD11B5 which are the enzymes that take part in the next step in the pathway. 11KAST is now either converted to 11K3α-diol by HSD11B3 or HSD11B5 (also known as AKR1C3) or it may be converted to 11K-5αdione by the 3α-oxidation activity of HSD11B6, depending on enzyme expression levels and steroidogenic tissue. <nowiki>11KDHT is subsequently biosynthesised from both 5α-androstane-3α,17β-diol-11-one (11K3α-diol) and 5α-androstane-3,11,17-trione (11K-5αdione). 11K3α-diol is converted by HSD11B6 and 11K-5αdione is converted by HSD11B3 and HSD11B5. In addition, 11KDHT can be converted to 11OHDHT by HSD11B1.}}</nowiki> These pathways leading to the production of 11KT, 11KDHT and 11OHDHT from progesterone and 21-dF, also elucidated previously by Barnard et al.<ref name="pmid33539964" /> in a 2021 review, can be outlined as shown on Figure 4. The order of steps in metabolic routes of the 11-oxygenated pregnanes towards 11-oxygenated androgens (11KDHT and 11OHDHT) is similar, in part, to 17-OHP's conversion to DHT in a backdoor pathway – the same enzymes catalyze the reactions mostly in the same sequence.<ref name="pmid28774496" /><ref name="pmid29277707" /><ref name="pmid33539964" /> However, in the biosynthesis of 11-oxygenated androgens and 11-oxygenated pregnanes, additional key enzymes for the initial reactions, are CYP11B1/CYP11B2 and HSD11B1/HSD11B2<ref name="pmid29277707" /><ref name="pmid23685396" /><ref name="pmid30825506" /> – with CYP11B1/CYP11B2 expressed primarily in adrenals together with low levels of HSD11B1/HSD11B2<ref name="pmid23386646">{{cite journal |title=Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation |journal=J Clin Endocrinol Metab |volume=98 |issue=3 |pages=1182–8 |pmid=23386646 |pmc=3590473 |doi=10.1210/jc.2012-2912|last1=Rege |first1=Juilee |last2=Nakamura |first2=Yasuhiro |last3=Satoh |first3=Fumitoshi |last4=Morimoto |first4=Ryo |last5=Kennedy |first5=Michael R. |last6=Layman |first6=Lawrence C. |last7=Honma |first7=Seijiro |last8=Sasano |first8=Hironobu |last9=Rainey |first9=William E. |year=2013 }}</ref> which are more abundantly expressed in peripheral tissue. Once converted by 5α-reductase, the pathway followed is similar to that of the backdoor steroidogenesis pathway leading ultimately to 11KDHT. ==Clinical Significance == === Biological Role of 11-Oxygenated Androgens === 11-oxygenated androgens are produced in physiological quantities in healthy primate organisms (including humans).<ref name="pmid30959151" /><ref name="pmid30753518" /><ref name="pmid32629108" /> Since the first step in the biosynthesis of 11-oxygenated androgens involves 11β-hydroxylation of a steroid substrate by CYP11B1/CYP11B2 isozymes that are generally associated with their expression in the adrenal gland, 11-oxygenated androgens are considered androgens of adrenal origin. They follow the circadian rhythm of cortisol but correlate very weakly with T, which further supports their adrenal origin.<ref name="pmid34867794">{{cite journal |title=24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=751191 |pmid=34867794 |pmc=8636728 |doi=10.3389/fendo.2021.751191 |doi-access=free |last1=Turcu |first1=Adina F. |last2=Mallappa |first2=Ashwini |last3=Nella |first3=Aikaterini A. |last4=Chen |first4=Xuan |last5=Zhao |first5=Lili |last6=Nanba |first6=Aya T. |last7=Byrd |first7=James Brian |last8=Auchus |first8=Richard J. |last9=Merke |first9=Deborah P. |year=2021 }}</ref><ref name="pmid34324429">{{cite journal|title=Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men |journal=Eur J Endocrinol |volume=185 |issue=4 |pages=K1–K6 |pmid=34324429 |doi=10.1530/EJE-21-0348 |pmc=8826489 |pmc-embargo-date=August 27, 2022 |last1=Turcu |first1=Adina F. |last2=Zhao |first2=Lili |last3=Chen |first3=Xuan |last4=Yang |first4=Rebecca |last5=Rege |first5=Juilee |last6=Rainey |first6=William E. |last7=Veldhuis |first7=Johannes D. |last8=Auchus |first8=Richard J. |year=2021 }}</ref> The levels of 11-oxygenated androgens are regulated by ACTH.<ref name="pmid23386646"/> However, in addition to the adrenal glands, CYP11B1 is also expressed in Leydig cells and ovarian theca cells, albeit at far lower levels, so the production of 11KT precursors may be one of the most important functions of 11β-hydroxylase activity in the gonads.<ref name="pmid27428878">{{cite journal|title=11-Ketotestosterone Is a Major Androgen Produced in Human Gonads |journal=J Clin Endocrinol Metab |volume=101 |issue=10 |pages=3582–3591 |pmid=27428878 |doi=10.1210/jc.2016-2311 |last1=Imamichi |first1=Yoshitaka |last2=Yuhki |first2=Koh-Ichi |last3=Orisaka |first3=Makoto |last4=Kitano |first4=Takeshi |last5=Mukai |first5=Kuniaki |last6=Ushikubi |first6=Fumitaka |last7=Taniguchi |first7=Takanobu |last8=Umezawa |first8=Akihiro |last9=Miyamoto |first9=Kaoru |last10=Yazawa |first10=Takashi |year=2016 }}</ref> Both isozymes have been shown to convert Δ⁴ steroids: P4, 17-OHP, A4 and T.<ref name="pmid23322723">{{cite journal |pmc=5417327|year=2013|last1=Strushkevich|first1=N.|last2=Gilep|first2=A. A.|last3=Shen|first3=L.|last4=Arrowsmith|first4=C. H.|last5=Edwards|first5=A. M.|last6=Usanov|first6=S. A.|last7=Park|first7=H. W.|title=Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition|journal=Molecular Endocrinology (Baltimore, Md.)|volume=27|issue=2|pages=315–324|doi=10.1210/me.2012-1287|pmid=23322723}}</ref> 11KT may serve as a primary androgen for healthy women,<ref name="pmid32629108">{{cite journal|last1=Barnard|first1=Lise|last2=Nikolaou|first2=Nikolaos|last3=Louw|first3=Carla|last4=Schiffer|first4=Lina|last5=Gibson|first5=Hylton|last6=Gilligan|first6=Lorna C.|last7=Gangitano|first7=Elena|last8=Snoep|first8=Jacky|last9=Arlt|first9=Wiebke|year=2020|title=The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1|url=|journal=The Journal of Steroid Biochemistry and Molecular Biology|volume=202|pages=105724|doi=10.1016/j.jsbmb.2020.105724|pmid=32629108|s2cid=220323715|last10=Tomlinson|first10=Jeremy W.|last11=Storbeck|first11=Karl-Heinz}}</ref><ref name="pmid30753518" /> as it circulates at similar levels to T, but unlike T, the levels of 11KT are stable across the menstrual cycle.<ref name="pmid31390028">{{cite journal|last1=Skiba|first1=Marina A.|last2=Bell|first2=Robin J.|last3=Islam|first3=Rakibul M.|last4=Handelsman|first4=David J.|last5=Desai|first5=Reena|last6=Davis|first6=Susan R.|year=2019|title=Androgens During the Reproductive Years: What Is Normal for Women?|journal=J Clin Endocrinol Metab|volume=104|issue=11|pages=5382–5392|doi=10.1210/jc.2019-01357|pmid=31390028|s2cid=199467054}}</ref> There are conflicting reports on whether 11-oxygenated androgens decline in women with age, and whether the relative contribution of 11KT as compared with T is higher in postmenopausal women than in younger ones — Nanba et al. (2019)<ref name="pmid30753518" /> and Davio et al. (2020)<ref name="pmid32498089">{{cite journal|last1=Davio|first1=Angela|last2=Woolcock|first2=Helen|last3=Nanba|first3=Aya T.|last4=Rege|first4=Juilee|last5=o'Day|first5=Patrick|last6=Ren|first6=Jianwei|last7=Zhao|first7=Lili|last8=Ebina|first8=Hiroki|last9=Auchus|first9=Richard|year=2020|title=Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood|journal=J Clin Endocrinol Metab|volume=105|issue=8|pages=e2921–e2929|doi=10.1210/clinem/dgaa343|pmc=7340191|pmid=32498089|last10=Rainey|first10=William E.|last11=Turcu|first11=Adina F.}}</ref> found that 11KT do not decline with age in women, however, Skiba et al. (2019)<ref name="pmid31390028" /> reported that the levels do decline. The decline of circulating 11-androgens with age may be associated with declining levels of DHEA and A4 which serve as precursors, since about half of circulating A4 quantities and almost all DHEA quantities are of adrenal origin.<ref name="pmid25428847">{{cite journal |vauthors=Turcu A, Smith JM, Auchus R, Rainey WE |title=Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions |journal=Compr Physiol |volume=4 |issue=4 |pages=1369–81 |date=October 2014 |pmid=25428847 |pmc=4437668 |doi=10.1002/cphy.c140006 |url=}}</ref> In a 2021 study, Schiffer et al. identified 11KT biosynthesis in human peripheral blood mononuclear cells (in blood samples), which produced eight times the amount of 11KT compared to T. The lag time before isolation of cellular components from whole blood increased serum 11KT concentrations in a time-dependent manner, with a significant increase observed from two hours after blood collection. These results emphasize that care should be taken when performing lab tests—to avoid falsely elevated 11KT levels.<ref name="pmid33444228">{{cite journal |title=Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens |journal=Eur J Endocrinol |volume=184 |issue=3 |pages=353–363 |pmid=33444228 |pmc=7923147 |doi=10.1530/EJE-20-1077| last1=Schiffer|first1=Lina|last2=Bossey|first2=Alicia|last3=Kempegowda|first3=Punith|last4=Taylor|first4=Angela E.|last5=Akerman|first5=Ildem|last6=Scheel-Toellner|first6=Dagmar|last7=Storbeck|first7=Karl-Heinz|last8=Arlt|first8=Wiebke|year=2021 |issn=1479-683X}}</ref> === Hyperandrogenism === Alternative androgen pathways are not always considered in the clinical evaluation of patients with hyperandrogenism, i.e., androgen excess.<ref name="pmid32610579">{{cite journal |title=Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report |journal=Int J Mol Sci |year=2020 |volume=21 |issue=13 |pmid=32610579 |pmc=7369945 |doi=10.3390/ijms21134622 |doi-access=free |last1=Sumińska |first1=Marta |last2=Bogusz-Górna |first2=Klaudia |last3=Wegner |first3=Dominika |last4=Fichna |first4=Marta |page=4622 }}</ref> Hyperandrogenism may lead to symptoms like acne, hirsutism, alopecia, premature adrenarche, oligomenorrhea or amenorrhea, polycystic ovaries and infertility.<ref name="pmid16772149">{{cite journal | last1=Yildiz | first1=Bulent O. | title=Diagnosis of hyperandrogenism: clinical criteria | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=20 | issue=2 | year=2006 | issn=1521-690X | pmid=16772149 | doi=10.1016/j.beem.2006.02.004 | pages=167–176}}</ref><ref name="pmid24184282">{{cite journal | last1=Peigné | first1=Maëliss | last2=Villers-Capelle | first2=Anne | last3=Robin | first3=Geoffroy | last4=Dewailly | first4=Didier | title=Hyperandrogénie féminine | journal=Presse Medicale (Paris, France) | publisher=Elsevier BV | volume=42 | issue=11 | year=2013 | issn=0755-4982 | pmid=24184282 | doi=10.1016/j.lpm.2013.07.016 | pages=1487–1499 | s2cid=28921380 | language=fr}}</ref> Relying on T levels alone in conditions associated with hyperandrogenism may read to diagnostic pitfalls and confusion.<ref name="pmid32610579"/> Despite the prevailing dogma that T and DHT are the primary human androgens, this paradigm applies only to healthy men.<ref name="pmid28234803">{{cite journal|title=Clinical significance of 11-oxygenated androgens |journal=Curr Opin Endocrinol Diabetes Obes |volume=24 |issue=3 |pages=252–259 |pmid=28234803 |pmc=5819755 |doi=10.1097/MED.0000000000000334 |last1=Turcu |first1=Adina F. |last2=Auchus |first2=Richard J. |year=2017 }}</ref> Although T has been traditionally used as a biomarker of androgen excess,<ref name="pmid32912651">{{cite journal|title=The predictive value of total testosterone alone for clinical hyperandrogenism in polycystic ovary syndrome |journal=Reprod Biomed Online |volume=41 |issue=4 |pages=734–742 |pmid=32912651 |doi=10.1016/j.rbmo.2020.07.013 |s2cid=221625488 |last1=Yang |first1=Yabo |last2=Ouyang |first2=Nengyong |last3=Ye |first3=Yang |last4=Hu |first4=Qin |last5=Du |first5=Tao |last6=Di |first6=Na |last7=Xu |first7=Wenming |last8=Azziz |first8=Ricardo |last9=Yang |first9=Dongzi |last10=Zhao |first10=Xiaomiao |year=2020 }}</ref> it correlates poorly with clinical findings of androgen excess.<ref name="pmid28234803"/> If the levels of T appear to be normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by very potent androgens such as DHT produced by a backdoor pathway and 11-oxygenated androgens also produced from 21-carbon steroid (pregnane) precursors in a backdoor pathway.<ref name="pmid33415088">{{cite journal | last1=Balsamo | first1=Antonio | last2=Baronio | first2=Federico | last3=Ortolano | first3=Rita | last4=Menabo | first4=Soara | last5=Baldazzi | first5=Lilia | last6=Di Natale | first6=Valeria | last7=Vissani | first7=Sofia | last8=Cassio | first8=Alessandra | title=Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant | journal=Frontiers in Pediatrics | year=2020 | publisher=Frontiers Media SA | volume=8 | page=593315 | issn=2296-2360 | pmid=33415088 | pmc=7783414 | doi=10.3389/fped.2020.593315| doi-access=free }}</ref><ref name="pmid29277706">{{cite journal | last1=Kamrath | first1=Clemens | last2=Wettstaedt | first2=Lisa | last3=Boettcher | first3=Claudia | last4=Hartmann | first4=Michaela F. | last5=Wudy | first5=Stefan A. | title=Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia | journal=The Journal of Steroid Biochemistry and Molecular Biology | publisher=Elsevier BV | volume=178 | year=2018 | issn=0960-0760 | pmid=29277706 | doi=10.1016/j.jsbmb.2017.12.016 | pages=221–228| s2cid=3709499 }}</ref> Another issue with the use of T as a biomarker of androgen excess is the low circulating levels in women and the specificity and sensitivity of the assays used.<ref name="pmid29306916">{{cite journal |title=Falsely elevated plasma testosterone concentrations in neonates: importance of LC-MS/MS measurements |journal=Clin Chem Lab Med |volume=56 |issue=6 |pages=e141–e143 |pmid=29306916 |doi=10.1515/cclm-2017-1028 |last1=Hamer |first1=Henrike M. |last2=Finken |first2=Martijn J.J. |last3=Van Herwaarden |first3=Antonius E. |last4=Du Toit |first4=Therina |last5=Swart |first5=Amanda C. |last6=Heijboer |first6=Annemieke C. |year=2018 |hdl=10019.1/106715 |s2cid=13917408 }}</ref><ref name="pmid32912651" /><ref name="pmid30753518">{{cite journal|last1=Nanba|first1=Aya T.|last2=Rege|first2=Juilee|last3=Ren|first3=Jianwei|last4=Auchus|first4=Richard J.|last5=Rainey|first5=William E.|last6=Turcu|first6=Adina F.|year=2019|title=11-Oxygenated C19 Steroids Do Not Decline With Age in Women|journal=J Clin Endocrinol Metab|volume=104|issue=7|pages=2615–2622|doi=10.1210/jc.2018-02527|pmc=6525564|pmid=30753518}}</ref> It had been suggested that 11β-hydroxyandrostenedione (11OHA4) and its urinary metabolites could have clinical applications used as a biomarkers of adrenal origin of androgen excess in women. Increased adrenal 11OHA4 production was characterised, using changes in A4:11OHA4 and 11β-hydroxyandrosterone:11β-hydroxyetiocholanolone ratios, in cushing syndrome, hirsutism, CAH and PCOS.<ref name="pmid1623996">{{cite journal|title=The ratio of androstenedione:11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women |journal=Fertil Steril |volume=58 |issue=1 |pages=148–52 |pmid=1623996 |doi=10.1016/s0015-0282(16)55152-8 |last1=Carmina |first1=E. |last2=Stanczyk |first2=F. Z. |last3=Chang |first3=L. |last4=Miles |first4=R. A. |last5=Lobo |first5=R. A. |year=1992 }}</ref><ref name="pmid14417423">{{cite journal |title=Urinary ketosteroids and pregnanetriol in hirsutism |journal=J Clin Endocrinol Metab |volume=20 |issue= 2|pages=180–6 |pmid=14417423 |doi=10.1210/jcem-20-2-180|last1=Lipsett |first1=Mortimer B. |last2=Riter |first2=Barbara |year=1960 }}</ref><ref name="pmid33340399" /><ref name="pmid3129451">{{cite journal|title=Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries |journal=J Clin Endocrinol Metab |volume=66 |issue=5 |pages=946–50 |pmid=3129451 |doi=10.1210/jcem-66-5-946 |last1=Polson |first1=D. W. |last2=Reed |first2=M. J. |last3=Franks |first3=S. |last4=Scanlon |first4=M. J. |last5=James |first5=V. H. T. |year=1988 }}</ref> However, due to to conflicting reports ratios did not find a firm footing in the clinical as a diagnostic tool. === On The Aromatization of Androgens === Unlike T and A4, 11-oxygenated androgens are unlikely to be converted by aromatase into estrogens ''in vivo'',<ref name="pmid32862221">{{cite journal |last1=Nagasaki |first1=Keisuke |last2=Takase |first2=Kaoru |last3=Numakura |first3=Chikahiko |last4=Homma |first4=Keiko |last5=Hasegawa |first5=Tomonobu |last6=Fukami |first6=Maki |title=Foetal virilisation caused by overproduction of non-aromatisable 11-oxy C19 steroids in maternal adrenal tumour |journal=Human Reproduction |year=2020 |volume=35 |issue=11 |pages=2609–2612 |doi=10.1093/humrep/deaa221 |pmid=32862221 }}</ref><ref name="pmid33340399">{{cite journal|title = 11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool | journal = Endocrinology | volume = 162 | issue = 3 | pmid = 33340399 | pmc = 7814299 | doi = 10.1210/endocr/bqaa231 | last1 = Barnard | first1 = Lise | last2 = Schiffer | first2 = Lina | last3 = Louw Du-Toit | first3 = Renate | last4 = Tamblyn | first4 = Jennifer A. | last5 = Chen | first5 = Shiuan | last6 = Africander | first6 = Donita | last7 = Arlt | first7 = Wiebke | last8 = Foster | first8 = Paul A. | last9 = Storbeck | first9 = Karl-Heinz |year = 2021 }}</ref> that was first predicted in 2016 by Imamichi at al. in an ''in vitro'' study.<ref name="pmid22170725">{{cite journal|last1=Kamrath|first1=Clemens|last2=Hochberg|first2=Ze'ev|last3=Hartmann|first3=Michaela F.|last4=Remer|first4=Thomas|last5=Wudy|first5=Stefan A.|title=Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis|url=https://pubmed.ncbi.nlm.nih.gov/22170725|journal=The Journal of Clinical Endocrinology and Metabolism|year=2012 |volume=97|issue=3|pages=E367–375|doi=10.1210/jc.2011-1997|issn=1945-7197|pmid=22170725|s2cid=3162065 }}</ref> The inability of aromatase to convert the 11-oxygenated androgens to estrogens may contribute to the 11-oxygenated androgens circulating at higher levels than other androgens in women when not taking into account DHEA. However, DHEA has a very low affinity for the androgen receptor and thus should not be an important contributor, if at all, for receptor activation under normal conditions.<ref name="pmid15994348">{{cite journal | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | year = 2005 | volume = 146 | issue = 11 | pages = 4568–76 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free | last1 = Chen | first1 = Fang | last2 = Knecht | first2 = Kristin | last3 = Birzin | first3 = Elizabeth | last4 = Fisher | first4 = John | last5 = Wilkinson | first5 = Hilary | last6 = Mojena | first6 = Marina | last7 = Moreno | first7 = Consuelo Tudela | last8 = Schmidt | first8 = Azriel | last9 = Harada | first9 = Shun-Ichi | last10 = Freedman | first10 = Leonard P. | last11 = Reszka | first11 = Alfred A. }}</ref><ref name="pmid16159155">{{cite journal |title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u | last1 = Gao | first1 = Wenqing | last2 = Bohl | first2 = Casey E. | last3 = Dalton | first3 = James T. | year = 2005 }}</ref> In a 2021 study, Barnard et al., incubating ''in vitro'' three different aromatase-expressing cell cultures and ''ex vivo'' human placenta explant cultures with normal and radiolabeled steroids, detected conversion of 11-oxygenated and conventional androgens into 11-oxygenated estrogens; however, 11-oxyegenated strogens were not detected ''in vivo'': neither in pregnant women who have high aromatase expression nor in patients who have high 11-androgens levels due to with congenital adrenal hyperplasia or adrenocortical carcinoma, probably due to relatively low aromatase activity towards 11-oxygenated androgens compared to classical androgens.<ref name="pmid33340399"/> However, it is possible that 11-oxyegenated strogens may be produced in some conditions such as feminizing adrenal carcinoma.<ref name="MAHESH196351">{{cite journal|title = Isolation of estrone and 11β-hydroxy estrone from a feminizing adrenal carcinoma | journal = Steroids | volume = 1 | number = 1 | pages = 51–61 |year = 1963 |issn = 0039-128X| doi = 10.1016/S0039-128X(63)80157-9 | url = https://www.sciencedirect.com/science/article/pii/S0039128X63801579 |first1=Virendra |last1=Mahesh |first2=Walter |last2=Herrmann}}</ref> DHT, an androgen that can also be produced in a backdoor pathway, is also a non-aromatizable androgen.<ref name="pmid2943941">{{cite journal |title=Stimulation of aromatase activity by dihydrotestosterone in human skin fibroblasts |journal=J Steroid Biochem |volume=25 |issue=1 |pages=165–9 |year=1986 |pmid=2943941 |doi=10.1016/0022-4731(86)90296-7 |last1=Chabab |first1=Aziz |last2=Sultan |first2=Charles |last3=Fenart |first3=Odile |last4=Descomps |first4=Bernard }}</ref><ref name="pmid10332569">{{cite journal |title=Dihydrotestosterone: a rationale for its use as a non-aromatizable androgen replacement therapeutic agent |journal=Baillieres Clin Endocrinol Metab |volume=12 |issue=3 |pages=501–6 |year=1998 |pmid=10332569 |doi=10.1016/s0950-351x(98)80267-x |last1=Swerdloff |first1=Ronald S. |last2=Wang |first2=Christina }}</ref> Therefore, the role of DHT and 11-oxygenated androgen should be seriously considered in women patients. === Disorders of Sex Development === Since both the canonical and backdoor pathways of androgen biosynthesis towards DHT lead to early male sexual differentiation<ref name="pmid30763313" /><ref name="pmid30943210">{{cite journal|title = The "backdoor pathway" of androgen synthesis in human male sexual development | journal = PLOS Biology | volume = 17 | issue = 4 | pages = e3000198 | pmid = 30943210 | pmc = 6464227 | doi = 10.1371/journal.pbio.3000198 | last1 = Miller | first1 = Walter L. | last2 = Auchus | first2 = Richard J. |year = 2019 }}</ref><ref name="pmid11035809" /><ref name="pmid15249131" /> and are required for normal human male genital development,<ref name="pmid30943210" /><ref name="pmid35793998">{{cite journal|last1=Lee|first1=Hyun Gyung|last2=Kim|first2=Chan Jong|year=2022|title=Classic and backdoor pathways of androgen biosynthesis in human sexual development|journal=Ann Pediatr Endocrinol Metab|volume=27|issue=2|pages=83–89|doi=10.6065/apem.2244124.062|pmid=35793998|s2cid=250155674}}</ref> deficiencies in the backdoor pathway to DHT from 17-OHP or from P4<ref name="pmid21802064"/><ref name="pmid23073980">{{cite journal|last1=Fukami|first1=Maki|last2=Homma|first2=Keiko|last3=Hasegawa|first3=Tomonobu|last4=Ogata|first4=Tsutomu|year=2013|title=Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development|journal=Developmental Dynamics|volume=242|issue=4|pages=320–9|doi=10.1002/dvdy.23892|pmid=23073980|s2cid=44702659}}</ref> lead to underverilization of male fetuses,<ref name="pmid24793988">{{cite journal |title=Steroidogenesis of the testis -- new genes and pathways |journal=Ann Endocrinol (Paris) |volume=75 |issue=2 |pages=40–7 |year=2014 |pmid=24793988 |doi=10.1016/j.ando.2014.03.002 |last1=Flück |first1=Christa E. |last2=Pandey |first2=Amit V. }}</ref><ref name="pmid8636249">{{cite journal |title=Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency |journal=J Clin Endocrinol Metab |volume=81 |issue=2 |pages=457–9 |year=1996 |pmid=8636249 |doi=10.1210/jcem.81.2.8636249 |url=|last1=Zachmann |first1=M. }}</ref> as placental P4 acts as a substrate during the biosynthesis of DHT in the backdoor pathway.<ref name="pmid30763313"/> Flück et al. described in 2011 a case of five 46,XY (male) patients from two families with DSD, caused by mutations in AKR1C2 and/or AKR1C4, an enzyme required for a backdoor pathway to DHT, but not the canonical pathway of androgen biosynthesis. In these patients, mutations in the AKR1C1 and AKR1C3 were excluded, and disorders in the canonical pathway of androgen biosynthesis have also been excluded, however, they had genital ambiguity. The 46,XX (female) relatives of affected patients, having the same mutations, were phenotypically normal and fertile. These findings confirmed that DHT produced in a backdoor pathway, while not necessary for the sexual development of females, is important for that of males. Although both AKR1C2 and AKR1C4 are needed for DHT synthesis in a backdoor pathway (Figure 2), the study found that mutations in AKR1C2 only were enough to disrupt it.<ref name="pmid21802064"/> However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.<ref name="pmid34711511">{{cite journal |title=Rare forms of genetic steroidogenic defects affecting the gonads and adrenals |journal=Best Pract Res Clin Endocrinol Metab |volume=36 |issue=1 |pages=101593 |year=2022 |pmid=34711511 |doi=10.1016/j.beem.2021.101593}}</ref> Isolated 17,20-lyase deficiency syndrome due to variants in CYP17A1, cytochrome b₅, and POR may also disrupt a backdoor pathway to DHT, as the 17,20-lyase activity of CYP17A1 is required for both canonical and backdoor androgen pathways (Figure 2). As such, this syndrome leads to DSD in both sexes, while affected girls go usually unrecognized until puberty, when they show amenorrhea. This syndrome is also rare with only a few cases reported.<ref name="pmid34711511"/> Besides that, 11-oxygenated androgens may play previously overlooked role in DSD.<ref name="pmid34171490">{{cite journal |title=Turning the spotlight on the C11-oxy androgens in human fetal development |journal=J Steroid Biochem Mol Biol |volume=212 |issue= |pages=105946 |pmid=34171490 |doi=10.1016/j.jsbmb.2021.105946|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2021 |s2cid=235603586 }}</ref><ref name="pmid34987475">{{cite journal|title=Disorders of Sex Development of Adrenal Origin |journal=Front Endocrinol (Lausanne) |volume=12 |issue= |pages=770782 |pmid=34987475 |pmc=8720965 |doi=10.3389/fendo.2021.770782 |doi-access=free |last1=Finkielstain |first1=Gabriela P. |last2=Vieites |first2=Ana |last3=Bergadá |first3=Ignacio |last4=Rey |first4=Rodolfo A. |year=2021 }}</ref><ref name="pmid31611378">{{cite journal|last1=Reisch|first1=Nicole|last2=Taylor|first2=Angela E.|last3=Nogueira|first3=Edson F.|last4=Asby|first4=Daniel J.|last5=Dhir|first5=Vivek|last6=Berry|first6=Andrew|last7=Krone|first7=Nils|last8=Auchus|first8=Richard J.|last9=Shackleton|first9=Cedric H. L.|title=Alternative pathway androgen biosynthesis and human fetal female virilization|journal=Proceedings of the National Academy of Sciences of the United States of America|year=2019 |volume=116|issue=44|pages=22294–22299|doi=10.1073/pnas.1906623116|issn=1091-6490|pmc=6825302|pmid=31611378|doi-access=free }}</ref> === Congenital Adrenal Hyperplasia === Another cause of androgen excess is congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol biosynthesis<ref name="pmid28576284">{{cite journal |vauthors=El-Maouche D, Arlt W, Merke DP |title=Congenital adrenal hyperplasia |journal=Lancet |volume=390 |issue=10108 |pages=2194–2210 |date=November 2017 |pmid=28576284 |doi=10.1016/S0140-6736(17)31431-9 |url=}}</ref> caused by a deficiency in any of the enzyme required to produce cortisol in the adrenal.<ref name="pmid12930931">{{cite journal |vauthors=Speiser PW, White PC |title=Congenital adrenal hyperplasia |journal=N Engl J Med |volume=349 |issue=8 |pages=776–88 |date=August 2003 |pmid=12930931 |doi=10.1056/NEJMra021561 |url=}}</ref><ref name="pmid30272171">{{cite journal | title = Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 103 | issue = 11 | pages = 4043–4088 | year = 2018 | pmid = 30272171 | pmc = 6456929 | doi = 10.1210/jc.2018-01865 }}</ref> Such deficiency leads to an excessive accumulation of a respective cortisol precursor, that becomes to serve as a substrate to androgens. In CYP21A2 deficiency<ref name="pmid22170725" /> including the mild forms (which are not always diagnosed)<ref name="pmid32966723">{{cite journal |vauthors=Merke DP, Auchus RJ |title=Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency |journal=N Engl J Med |volume=383 |issue=13 |pages=1248–1261 |date=September 2020 |pmid=32966723 |doi=10.1056/NEJMra1909786 |url=}}</ref><ref name="pmid31499506">{{cite book|title=Hyperandrogenism in Women|last1=Pignatelli|first1=Duarte|last2=Pereira|first2=Sofia S.|last3=Pasquali|first3=Renato|year=2019|isbn=978-3-318-06470-4|series=Frontiers of Hormone Research|volume=53|pages=65–76|chapter=Androgens in Congenital Adrenal Hyperplasia|doi=10.1159/000494903|pmid=31499506|s2cid=202412336}}</ref> or cytochrome P450 oxidoreductase (POR) deficiency,<ref name="pmid31611378" /><ref name="pmid35793998" /> elevated 17-OHP levels starts the backdoor pathway to DHT. This pathway may be activated regardless of age and sex.<ref name="pmid26038201">{{cite journal|last1=Turcu|first1=Adina F.|last2=Auchus|first2=Richard J.|year=2015|title=Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia|journal=Endocrinology and Metabolism Clinics of North America|publisher=Elsevier BV|volume=44|issue=2|pages=275–296|doi=10.1016/j.ecl.2015.02.002|issn=0889-8529|pmc=4506691703046|pmid=26038201}}</ref> The reason why 17-OHP serves as a prerequisite substrate for DHT within the backdoor pathway roundabout of T rather then an immediate substrate within the Δ⁴ pathway for A4, and then T, is because the catalytic activity 17,20-lyase reaction (which cleaves a side-chain from the steroid nucleus converting a pregnane to an androstane (androgen), i.e., from 17OPH5 to DHEA; from 17-OHP to A4) performed by CYP17A1 in humans is approximately 100 times more efficient in the Δ⁵ pathway than in the Δ⁴ pathway. Therefore, the catalytic efficiency of CYP17A1 for 17-OHP is about 100 times lower than for 17OHP5, resulting in negligible A4 being produced from 17-OHP in the Δ⁴ reaction pathway in humans.<ref name="pmid8325965">{{cite journal|last1=Swart|first1=P.|last2=Swart|first2=A. C.|last3=Waterman|first3=M. R.|last4=Estabrook|first4=R. W.|last5=Mason|first5=J. I.|year=1993|title=Progesterone 16 alpha-hydroxylase activity is catalyzed by human cytochrome P450 17 alpha-hydroxylase|journal=J Clin Endocrinol Metab|volume=77|issue=1|pages=98–102|doi=10.1210/jcem.77.1.8325965|pmid=8325965}}</ref><ref name="pmid12915666">{{cite journal|last1=Flück|first1=Christa E.|last2=Miller|first2=Walter L.|last3=Auchus|first3=Richard J.|year=2003|title=The 17, 20-lyase activity of cytochrome CYP17A1 from human fetal testis favors the delta5 steroidogenic pathway|url=https://pubmed.ncbi.nlm.nih.gov/12915666|journal=The Journal of Clinical Endocrinology and Metabolism|volume=88|issue=8|pages=3762–3766|doi=10.1210/jc.2003-030143|issn=0021-972X|pmid=12915666}}</ref><ref name="pmid15774560">{{cite journal|last1=Miller|first1=Walter L.|year=2005|title=Minireview: regulation of steroidogenesis by electron transfer|url=https://pubmed.ncbi.nlm.nih.gov/15774560|journal=Endocrinology|volume=146|issue=6|pages=2544–2550|doi=10.1210/en.2005-0096|issn=0013-7227|pmid=15774560}}</ref><ref name="pmid32007561"/> The accumulation of 17-OHP in CYP21A2 deficiency in CAH can be attributed to the fact that the primary enzyme for 17-OHP in normal conditions is CYP21A2, that is expressed in the adrenal and not the gonads.<ref name="pmid31450227">{{cite journal|last1=Miller|first1=Walter L.|title=Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol|url=https://pubmed.ncbi.nlm.nih.gov/31450227|journal=Hormone Research in Paediatrics|year=2019 |volume=91|issue=6|pages=416–420|doi=10.1159/000501396|issn=1663-2826|pmid=31450227|s2cid=201733086 }}</ref><ref name="pmid26038201"/> In a 1998 study, Auchus et al. demonstrated that human CYP17A1 efficiently catalyzed the conversion of P4 to 17-OHP, but the conversion of 17-OHP to A4 was much less efficient than the corresponding conversion of 17OHP5 to DHEA.<ref name="pmid9452426"/> In rodents, quite contrary, the conversion of 17-OHP to A4 is very efficient.<ref name="pmid9452426">{{cite journal | last1=Auchus | first1=Richard J. | last2=Lee | first2=Tim C. | last3=Miller | first3=Walter L. | title=Cytochrome b 5 Augments the 17,20-Lyase Activity of Human P450c17 without Direct Electron Transfer | journal=The Journal of Biological Chemistry | year=1998 | publisher=Elsevier BV | volume=273 | issue=6 | issn=0021-9258 | pmid=9452426 | doi=10.1074/jbc.273.6.3158 | pages=3158–3165| doi-access=free }}</ref> This explains significant accumulation of 17-OHP in CYP21A2 deficiency or POR deficiency in humans, so that 17-OHP, while not 21-hydroxylated in sufficient quantities, and being better a substrate for 5α-reductase than for CYP17A1, is 5α-reduced serving as the prerequisite for this backdoor pathway. Hence, fetal excess of 17-OHP in CAH may provoke activation of this pathway to DHT and lead to external genital virilization in newborn girls, thus explaining DSD in girls with CAH.<ref name="pmid31611378" /> P4 levels may also be elevated in CAH,<ref name="pmid25850025"/><ref name="pmid31505456">{{cite journal |vauthors=Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, Varnous S, Bachelot A, Salem JE |title=Influence of hormones on the immunotolerogenic molecule HLA-G: a cross-sectional study in patients with congenital adrenal hyperplasia |journal=Eur J Endocrinol |volume=181 |issue=5 |pages=481–488 |date=November 2019 |pmid=31505456 |doi=10.1530/EJE-19-0379 |url=}}</ref> leading to androgen excess via the backdoor pathway to DHT that starts with the same way as in the pathway that starts with 17-OHP.<ref name="pmid28188961">{{cite journal |vauthors=Kawarai Y, Ishikawa H, Segawa T, Teramoto S, Tanaka T, Shozu M |title=High serum progesterone associated with infertility in a woman with nonclassic congenital adrenal hyperplasia |journal=J Obstet Gynaecol Res |volume=43 |issue=5 |pages=946–950 |date=May 2017 |pmid=28188961 |doi=10.1111/jog.13288 |url=}}</ref> 17-OHP and P4 may also serve as substrates to 11-oxygenated androgens in CAH.<ref name="pmid28472487">{{cite journal | last1=Turcu | first1=Adina F | last2=Mallappa | first2=Ashwini | last3=Elman | first3=Meredith S | last4=Avila | first4=Nilo A | last5=Marko | first5=Jamie | last6=Rao | first6=Hamsini | last7=Tsodikov | first7=Alexander | last8=Auchus | first8=Richard J | last9=Merke | first9=Deborah P | title = 11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency | journal = The Journal of Clinical Endocrinology and Metabolism | year=2017 | volume = 102 | issue = 8 | pages = 2701–2710 | pmid = 28472487 | pmc = 5546849 | doi = 10.1210/jc.2016-3989}}</ref><ref name="pmid26865584">{{cite journal|title=Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency |journal=Eur J Endocrinol |volume=174 |issue=5 |pages=601–9 |pmid=26865584 |pmc=4874183 |doi=10.1530/EJE-15-1181 |last1=Turcu |first1=Adina F. |last2=Nanba |first2=Aya T. |last3=Chomic |first3=Robert |last4=Upadhyay |first4=Sunil K. |last5=Giordano |first5=Thomas J. |last6=Shields |first6=James J. |last7=Merke |first7=Deborah P. |last8=Rainey |first8=William E. |last9=Auchus |first9=Richard J. |year=2016 }}</ref><ref name="pmid29718004">{{cite journal|title = Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 25 | issue = 3 | pages = 178–184 | pmid = 29718004 | doi = 10.1097/MED.0000000000000402 | s2cid = 26072848 |last1 = White |first1 = Perrin C. |year = 2018 }}</ref><ref name="pmid34867794"/> In males with CAH, 11-oxygenated androgens may lead to devlopment of testicular adrenal rest tumors<ref name="pmid25850025">{{cite journal|pmc=4454804|year=2015|last1=Turcu|first1=A. F.|last2=Rege|first2=J.|last3=Chomic|first3=R.|last4=Liu|first4=J.|last5=Nishimoto|first5=H. K.|last6=Else|first6=T.|last7=Moraitis|first7=A. G.|last8=Palapattu|first8=G. S.|last9=Rainey|first9=W. E.|last10=Auchus|first10=R. J.|title=Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency|journal=The Journal of Clinical Endocrinology and Metabolism|volume=100|issue=6|pages=2283–2290|doi=10.1210/jc.2015-1023|pmid=25850025}}</ref><ref name="pmid28472487" /><ref name="pmid34390337">{{cite journal|title=Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors |journal=J Clin Endocrinol Metab |volume=107 |issue=1 |pages=e272–e280 |pmid=34390337 |pmc=8684463 |doi=10.1210/clinem/dgab598 |last1=Schröder |first1=Mariska A M. |last2=Turcu |first2=Adina F. |last3=o'Day |first3=Patrick |last4=Van Herwaarden |first4=Antonius E. |last5=Span |first5=Paul N. |last6=Auchus |first6=Richard J. |last7=Sweep |first7=Fred C G J. |last8=Claahsen-Van Der Grinten |first8=Hedi L. |year=2022 }}</ref> The biosynthesis of 11OHP4 from P4 and 21dF from 17-OHP by CYP11B1/CYP11B2 in CAH may be attributed to CYP21A2 deficiency resulting in increased P4 and 17-OHP concentrations and, together with the unavailability of CYP11B1/CYP11B2's main substrates, 11-deoxycortisol (11dF) and 11-deoxycorticosterone (DOC), drive the production of 11-oxygenated pregnanes.<ref name="pmid3546944" /> We have reasons to believe that this may be aggravated by elevated ACTH due to a feedback loop in hypothalamic-pituitary-adrenal axis caused by impaired cortisol synthesis associated with CYP21A2 deficiency; higher ACTH causes higher CYP11B1 expression. Multiple studies demonstrated that in CAH due to CYP21A2 deficiency, both 21dF levels<ref name="pmid4372245">{{cite journal |title=Plasma 17-hydroxyprogesterone, 21-deoxycortisol and cortisol in congenital adrenal hyperplasia |journal=J Clin Endocrinol Metab |volume=39 |issue=6 |pages=1099–102 |year=1974 |pmid=4372245 |doi=10.1210/jcem-39-6-1099 |last1=Franks |first1=Robert C. }}</ref><ref name="pmid476971">{{cite journal |title=Rapid assay of plasma 21-deoxycortisol and 11-deoxycortisol in congenital adrenal hyperplasia |journal=Clin Endocrinol (Oxf) |volume=10 |issue=4 |pages=367–75 |year=1979 |pmid=476971 |doi=10.1111/j.1365-2265.1979.tb02091.x |url=|last1=Fukushima |first1=D. K. |last2=Nishina |first2=T. |last3=Wu |first3=R. H. K. |last4=Hellman |first4=L. |last5=Finkelstein |first5=J. W. |s2cid=2979354 }}</ref><ref name="pmid6090811">{{cite journal |title=Development of plasma 21-deoxycortisol radioimmunoassay and application to the diagnosis of patients with 21-hydroxylase deficiency |journal=J Steroid Biochem |volume=21 |issue=2 |pages=185–91 |year=1984 |pmid=6090811 |doi=10.1016/0022-4731(84)90382-0 |last1=Milewicz |first1=A. |last2=Vecsei |first2=P. |last3=Korth-Schütz |first3=S. |last4=Haack |first4=D. |last5=Rösler |first5=A. |last6=Lichtwald |first6=K. |last7=Lewicka |first7=S. |last8=Mittelstaedt |first8=G.v. }}</ref><ref name="pmid2986404">{{cite journal |title=Radioimmunoassay for 21-deoxycortisol: clinical applications |journal=Acta Endocrinol (Copenh) |volume=108 |issue=4 |pages=537–44 |year=1985 |pmid=2986404 |doi=10.1530/acta.0.1080537 |last1=Gueux |first1=B. |last2=Fiet |first2=J. |last3=Pham-Huu-Trung |first3=M. T. |last4=Villette |first4=J. M. |last5=Gourmelen |first5=M. |last6=Galons |first6=H. |last7=Brerault |first7=J. L. |last8=Vexiau |first8=P. |last9=Julien |first9=R. }}</ref><ref name="pmid25850025" /> and 11OPH4 levels<ref name="pmid3546944">{{cite journal |last1=Gueux |first1=Bernard |last2=Fiet |first2=Jean |last3=Galons |first3=Hervé |last4=Boneté |first4=Rémi |last5=Villette |first5=Jean-Marie |last6=Vexiau |first6=Patrick |last7=Pham-Huu-Trung |first7=Marie-Thérèse |last8=Raux-Eurin |first8=Marie-Charles |last9=Gourmelen |first9=Micheline |last10=Brérault |first10=Jean-Louis |last11=Julien |first11=René |last12=Dreux |first12=Claude |title=The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma |journal=Journal of Steroid Biochemistry |year=1987 |volume=26 |issue=1 |pages=145–150 |doi=10.1016/0022-4731(87)90043-4 |pmid=3546944 }}</ref><ref name="pmid2537337">{{cite journal |last1=Fiet |first1=Jean |last2=Gueux |first2=Bernard |last3=Rauxdemay |first3=Marie-Charles |last4=Kuttenn |first4=Frederique |last5=Vexiau |first5=Patrick |last6=Brerault |first6=Jeanlouis |last7=Couillin |first7=Philippe |last8=Galons |first8=Herve |last9=Villette |first9=Jeanmarie |last10=Julien |first10=Rene |last11=Dreux |first11=Claude |title=Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway |journal=The Journal of Clinical Endocrinology & Metabolism |year=1989 |volume=68 |issue=3 |pages=542–547 |doi=10.1210/jcem-68-3-542 |pmid=2537337 }}</ref><ref name="pmid29264476">{{cite journal |last1=Fiet |first1=Jean |last2=Le Bouc |first2=Yves |last3=Guéchot |first3=Jérôme |last4=Hélin |first4=Nicolas |last5=Maubert |first5=Marie-Anne |last6=Farabos |first6=Dominique |last7=Lamazière |first7=Antonin |title=A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia |journal=Journal of the Endocrine Society |year=2017 |volume=1 |issue=3 |pages=186–201 |doi=10.1210/js.2016-1048 |pmid=29264476 |pmc=5686660 }}</ref><ref name="pmid31821037">{{cite journal |title=Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency |journal=Am J Physiol Endocrinol Metab |volume=318 |issue=2 |pages=E102–E110 |year=2020 |pmid=31821037 |doi=10.1152/ajpendo.00368.2019 |last1=Travers |first1=Simon |last2=Bouvattier |first2=Claire |last3=Fagart |first3=Jérôme |last4=Martinerie |first4=Laetitia |last5=Viengchareun |first5=Say |last6=Pussard |first6=Eric |last7=Lombès |first7=Marc |s2cid=209314028 }}</ref> are increased. It was Robert Franks in who first published a study, in 1974, that compared 21dF levels of CAH patients with those of healthy controls. He measured 21dF plasma levels in twelve CAH patients before treatment, three after treatment, and four healthy controls following ACTH administration. Mean values of 21dF in CAH patients was 88 ng/ml while in healthy controls it was not detected. In untreated patients, values decreased after therapy. Even that, there were earlier reports about case where 21dF was detected in CAH patients, but without direct comparison to healthy controls.<ref name="pmid5845501">{{cite journal |title=Detection of 21-deoxycortisol in blood from a patient with congenital adrenal hyperplasia |journal=Metabolism |year=1965 |volume=14 |issue=12 |pages=1276–81 |pmid=5845501 |doi=10.1016/s0026-0495(65)80008-7|last1=Wieland |first1=Ralph G. |last2=Maynard |first2=Donald E. |last3=Riley |first3=Thomas R. |last4=Hamwi |first4=George J. }}</ref><ref name="pmid13271547">{{cite journal|title=17alpha-hydroxyprogesterone and 21-desoxyhydrocortisone; their metabolism and possible role in congenital adrenal virilism |journal=J Clin Invest |volume=34 |issue=11 |pages=1639–46 |year=1955 |pmid=13271547 |pmc=438744 |doi=10.1172/JCI103217|last1=Jailer |first1=Joseph W. |last2=Gold |first2=Jay J. |last3=Vande Wiele |first3=Raymond |last4=Lieberman |first4=Seymour }}</ref> As for 11OHP4, it were Gueux et al. who first demonstrated, in 1987, elevated plasma levels of 11OHP4 in CAH. In that study, in treated classical CAH patients, some of which had salt-wasting form, mean levels of 11OHP4 (5908.7 pmol/l) were 332 times higher than in healthy controls (17.8 pmol/l). There was no difference in 11OHP4 in healthy controls depending on sex or phase of a menstrual cycle; ACTH stimulation in those control increased 11OHP4 four- to six-fold, while dexamethasone 1 mg at midnight decreased 11OHP4 to almost undetectable levels 12 hours later. Therefore, the authors hypothesized that at least in healthy people 11OHP4 is biosythesized exclusively in the adrenal, while gonads are not involved.<ref name="pmid3546944" /> Nevertheless, in studies focusing on CAH caused by CYP21A2 deficiency, 11OHP4 received less attention than 21dF.<ref name="pmid29277707"/> However, it was not until 2017 when 11OHP4 or 21dF were viewed as potential substrates in pathways towards potent 11-ogygenated androgens in ''in vitro'' studies.<ref name="pmid32007561"/><ref name="pmid29277707"/> === Polycystic Ovary Syndrome === In PCOS, DHT may be produced in a backdoor pathway from 17-OHP or P4 as consequence of abnormally upregulated SRD5A1.<ref name="pmid27471004">{{cite journal |title=Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome |journal=Mol Cell Endocrinol |volume=441 |issue= |pages=116–123 |pmid=27471004 |doi=10.1016/j.mce.2016.07.029|last1=Marti |first1=Nesa |last2=Galván |first2=José A. |last3=Pandey |first3=Amit V. |last4=Trippel |first4=Mafalda |last5=Tapia |first5=Coya |last6=Müller |first6=Michel |last7=Perren |first7=Aurel |last8=Flück |first8=Christa E. |year=2017 |s2cid=22185557 }}</ref><ref name="pmid1968168">{{cite journal|last1=Stewart|first1=P. M.|last2=Shackleton|first2=C. H.|last3=Beastall|first3=G. H.|last4=Edwards|first4=C. R.|title=5 alpha-reductase activity in polycystic ovary syndrome|url=https://pubmed.ncbi.nlm.nih.gov/1968168|journal=Lancet (London, England)|year=1990 |volume=335|issue=8687|pages=431–433|doi=10.1016/0140-6736(90)90664-q|issn=0140-6736|pmid=1968168|s2cid=54422650 }}</ref><ref name="pmid19567518">{{cite journal|title=Increased 5 alpha-reductase activity and adrenocortical drive in women with polycystic ovary syndrome |journal=J Clin Endocrinol Metab |volume=94 |issue=9 |pages=3558–66 |pmid=19567518 |doi=10.1210/jc.2009-0837 |last1=Vassiliadi |first1=Dimitra A. |last2=Barber |first2=Thomas M. |last3=Hughes |first3=Beverly A. |last4=McCarthy |first4=Mark I. |last5=Wass |first5=John A. H. |last6=Franks |first6=Stephen |last7=Nightingale |first7=Peter |last8=Tomlinson |first8=Jeremy W. |last9=Arlt |first9=Wiebke |last10=Stewart |first10=Paul M. |year=2009 }}</ref><ref name="pmid32247282">{{cite journal | last1=Swart | first1=Amanda C. | last2=du Toit | first2=Therina | last3=Gourgari | first3=Evgenia | last4=Kidd | first4=Martin | last5=Keil | first5=Meg | last6=Faucz | first6=Fabio R. | last7=Stratakis | first7=Constantine A. | title=Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS | journal=Pediatric Research | publisher=Springer Science and Business Media LLC | volume=89 | issue=1 | year=2021 | issn=0031-3998 | pmid=32247282 | pmc=7541460 | doi=10.1038/s41390-020-0870-1 | pages=118–126}}</ref> 11-oxygenated androgens may also play an important role in PCOS.<ref name="pmid35611324">{{cite journal |title=11-Oxyandrogens in Adolescents With Polycystic Ovary Syndrome |journal=J Endocr Soc |year=2022 |volume=6 |issue=7 |pages=bvac037|pmid=35611324 |pmc=9123281 |doi=10.1210/jendso/bvac037|last1=Taylor |first1=Anya E. |last2=Ware |first2=Meredith A. |last3=Breslow |first3=Emily |last4=Pyle |first4=Laura |last5=Severn |first5=Cameron |last6=Nadeau |first6=Kristen J. |last7=Chan |first7=Christine L. |last8=Kelsey |first8=Megan M. |last9=Cree-Green |first9=Melanie }}</ref><ref name="pmid32637065">{{cite journal |title=Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome |journal=Ther Adv Endocrinol Metab |volume=11 |issue= |pages=2042018820934319 |pmid=32637065 |pmc=7315669 |doi=10.1177/2042018820934319|last1=Kempegowda |first1=Punith |last2=Melson |first2=Eka |last3=Manolopoulos |first3=Konstantinos N. |last4=Arlt |first4=Wiebke |last5=o'Reilly |first5=Michael W. |year=2020 }}</ref><ref name="pmid27901631">{{cite journal|title=11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome |journal=J Clin Endocrinol Metab |volume=102 |issue=3 |pages=840–848 |pmid=27901631 |pmc=5460696 |doi=10.1210/jc.2016-3285 |last1=o'Reilly |first1=Michael W. |last2=Kempegowda |first2=Punith |last3=Jenkinson |first3=Carl |last4=Taylor |first4=Angela E. |last5=Quanson |first5=Jonathan L. |last6=Storbeck |first6=Karl-Heinz |last7=Arlt |first7=Wiebke |year=2017 }}</ref> In a 2017 study, O'Reilly et al. revealed that 11-oxygenated androgens are the predominant androgens in women with PCOS, while in healthy control subjects, classic androgens constitute the majority of the circulating androgen pool; nevertheless, the levels of 11KT exceeded those of T in both groups, specifically, 3.4 fold in the PCOS group. Besides that, the levels of 11OHA4 and 11KA4 correlated with the levels of markers of insulin resistance; therefore, the study suggests that androgen excess precedes androgen-driven insulin resistance in PCOS.<ref name="pmid27901631" /> While earlier studies had commonly only measured 11OHA4 or 11OHAST and 11β-hydroxyetiocholanolone (11OHEt), urinary metabolites of 11OHA,<ref name="pmid33539964" /> while 11OHEt is also a metabolite of cortisol,<ref name="pmid31362062">{{cite journal |title=Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review |journal=J Steroid Biochem Mol Biol |volume=194 |issue= |pages=105439 |year=2019 |pmid=31362062 |pmc=6857441 |doi=10.1016/j.jsbmb.2019.105439 |url=|last1=Schiffer |first1=Lina |last2=Barnard |first2=Lise |last3=Baranowski |first3=Elizabeth S. |last4=Gilligan |first4=Lorna C. |last5=Taylor |first5=Angela E. |last6=Arlt |first6=Wiebke |last7=Shackleton |first7=Cedric H.L. |last8=Storbeck |first8=Karl-Heinz }}</ref><ref name="pmid27845856">{{cite journal |title=Modified-Release and Conventional Glucocorticoids and Diurnal Androgen Excretion in Congenital Adrenal Hyperplasia |journal=J Clin Endocrinol Metab |volume=102 |issue=6 |pages=1797–1806 |year=2017 |pmid=27845856 |pmc=5470768 |doi=10.1210/jc.2016-2855|last1=Jones |first1=Christopher M. |last2=Mallappa |first2=Ashwini |last3=Reisch |first3=Nicole |last4=Nikolaou |first4=Nikolaos |last5=Krone |first5=Nils |last6=Hughes |first6=Beverly A. |last7=o'Neil |first7=Donna M. |last8=Whitaker |first8=Martin J. |last9=Tomlinson |first9=Jeremy W. |last10=Storbeck |first10=Karl-Heinz |last11=Merke |first11=Deborah P. |last12=Ross |first12=Richard J. |last13=Arlt |first13=Wiebke }}</ref> more recent investigations have reported circulating levels of 11KA4, 11KT and 11OHT levels in PCOS as well as 11-oxygenated pregnanes. In a 2016 study, Turcu et al. showed that in classic CAH due to CYP21A2 deficiency, in male and female patients who received glucocorticoid therapy, both conventional and 11-oxygenated androgens were elevated 3-4 fold compared to healthy controls. The exceptions were dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenediol sulfate (A5-S), whose levels were 6.0, 7.5, and 9.4 times lower, respectively, in the patients with the condition compared to healthy controls, due to suppression by glucocorticoid treatment. The levels of 11-oxygenated androgens correlated positively with conventional androgens in women but negatively in men. The levels of 11KT were 4 times higher compared to that of T in women with the condition.<ref name="pmid26865584" /> A subsequent study reported 11OHT was the only significantly elevated 11-oxygeated androgen in PCOS and together with 11KT, correlated with body mass index.<ref name="pmid30012903">{{cite journal |title=11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome |journal=Endocr J |volume=65 |issue=10 |pages=979–990 |pmid=30012903 |doi=10.1507/endocrj.EJ18-0212|last1=Yoshida |first1=Tomoko |last2=Matsuzaki |first2=Toshiya |last3=Miyado |first3=Mami |last4=Saito |first4=Kazuki |last5=Iwasa |first5=Takeshi |last6=Matsubara |first6=Yoichi |last7=Ogata |first7=Tsutomu |last8=Irahara |first8=Minoru |last9=Fukami |first9=Maki |year=2018 }}</ref> Significantly elevated 11KT levels have been detected in the daughters of PCOS mothers and in obese girls while 11OHA4, 11KA4 and 11OHT levels were comparable.<ref name="pmid32797203">{{cite journal |title=11-Oxygenated C19 Steroids Do Not Distinguish the Hyperandrogenic Phenotype of PCOS Daughters from Girls with Obesity |journal=J Clin Endocrinol Metab |volume=105 |issue=11 |pages= e3903–e3909 |pmid=32797203 |pmc=7500474 |doi=10.1210/clinem/dgaa532|last1=Torchen |first1=Laura C. |last2=Sisk |first2=Ryan |last3=Legro |first3=Richard S. |last4=Turcu |first4=Adina F. |last5=Auchus |first5=Richard J. |last6=Dunaif |first6=Andrea |year=2020 }}</ref> 11KT has also been shown to be elevated together with decreased 11KA4 levels in PCOS patients with micronodular adrenocortical hyperplasia. In addition 11OHAST, 11OHEt, DHP4 and 11KDHP4 levels were elevated and 11OHP4, 21dF and 11KDHP4 were elevated in patients with inadequate dexamethasone responses.<ref name="pmid31450227"/> Metformin treatment had no effect on 11-oxygenated androgens in PCOS adolescents in a 2022 study, despite lower levels of T after treatment.<ref name="pmid35611324" /> === Premature Adrenarche === In a 2018 study, Rege et al. demonstrated that levels of 11KT in girls aged between 4 and 7 years during normal adrenarche (healthy controls) exceeded those of T by 2.43 times, and in those with premature adrenarche by 3.48 times. However, the levels of T in girls with premature adrenarche were higher by just 13% compared to age-matched healthy controls.<ref name="pmid30137510">{{cite journal | last1=Rege | first1=Juilee | last2=Turcu | first2=Adina | last3=Kasa-Vubu | first3=Josephine Z | last4=Lerario | first4=Antonio M | last5=Auchus | first5=Gabriela C | last6=Auchus | first6=Richard J | last7=Smith | first7=Joshua M | last8=White | first8=Perrin C | last9=Rainey | first9=William E | title=11KT is the dominant circulating bioactive androgen during normal and premature adrenarche | journal=The Journal of Clinical Endocrinology and Metabolism | year=2018 | publisher=The Endocrine Society | volume=103 | issue=12 | pages=4589–4598 | issn=0021-972X | pmid=30137510 | pmc=6226603 | doi=10.1210/jc.2018-00736 }}</ref> === Castration-Resistant Prostate Cancer === In some cases of advanced prostate cancer, androgen deprivation therapy related to gonadal T depletion does not produce long-term effects, and metastatic tumors may develop into castration-resistant prostate cancer (CRPC). The development of CRPC depends on adrenal precursor steroids to produce DHT in the tumor in a metabolic pathway called the "5α-dione" pathway - the pathway in which T is not involved. SRD5A1, the expression of which increases in CRPC, 5α-reduces A4 to 5α-dione, which is then converted to DHT.<ref name="pmid21795608"/><ref name="pmid31900912"/> Therefore, the DHT produced within the "5α-dione" pathway hampers the androgen deprivation therapy. Although blood levels of T are reduced by 90-95% in men whose testicles have been removed, DHT in the prostate is only reduced by 50%, thus indicating the presence of a metabolic pathway in the prostate that does not require testicular T to produce DHT.<ref name="pmid18471780">{{cite journal | last1=Luu-The | first1=Van | last2=Bélanger | first2=Alain | last3=Labrie | first3=Fernand | title=Androgen biosynthetic pathways in the human prostate | journal=Best Practice & Research. Clinical Endocrinology & Metabolism | publisher=Elsevier BV | volume=22 | issue=2 | year=2008 | issn=1521-690X | pmid=18471780 | doi=10.1016/j.beem.2008.01.008 | pages=207–221}}</ref> Chang et al., incubating six established human prostate cancer cell lines from patients with CRPC in presence of radiolabeled A4, showed in their experiment published in 2011<ref name="pmid21795608">{{cite journal|last1=Chang | first1=K.-H. | last2=Li | first2=R. | last3=Papari-Zareei | first3=M. | last4=Watumull | first4=L. | last5=Zhao | first5=Y. D. | last6=Auchus | first6=R. J. | last7=Sharifi | first7=N. | title=Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer | journal=Proceedings of the National Academy of Sciences of the United States of America |year=2011 | publisher=Proceedings of the National Academy of Sciences | volume=108 | issue=33 | issn=0027-8424 | pmid=21795608 | pmc=3158152 | doi=10.1073/pnas.1107898108 | pages=13728–13733|bibcode=2011PNAS..10813728C |doi-access=free }}</ref> the presence of this pathway to DHT which bypasses T and they called this the "alternative" pathway, that became later commonly called as the "5α-dione" pathway.<ref name="pmid23856005"/> The authors demonstrated that this was the dominant pathway in prostate cancer (over the direct conversion of A4 to T) with SRD5A1 (which is upregulated in prostate cancer) first converting A4 to androstanedione (5α-dione), also known as 5α-androstane-3,17-dione, and then HSD17B3 / AKR1C3 converting 5α-dione to DHT (not necessarily via AST and 3α-diol). The study also found that the SRD5A2 is not involved in this "alternative" pathway.<ref name="pmid31900912"/> Therefore, the study showed the importance of taking into consideration this "alternative" pathway in selecting drugs that inhibit 5α-reductase activity.<ref name="pmid21901017">{{cite journal |title=Prostate cancer: DHT bypasses testosterone to drive progression to castration resistance |journal=Nat Rev Urol |volume=8 |issue=9 |pages=470 |year=September 2011 |pmid=21901017 |doi=10.1038/nrurol.2011.122 }}</ref><ref name="pmid22064602" /><ref name="pmid22336886">{{cite journal |title=Dihydrotestosterone synthesis from adrenal precursors does not involve testosterone in castration-resistant prostate cancer |journal=Cancer Biol Ther |volume=13 |issue=5 |pages=237–8 |year=2012 |pmid=22336886 |doi=10.4161/cbt.19608}}</ref> Another pathway that may be activated in CRPC, which may also hamper the androgen deprivation therapy, is the backdoor pathway from P4 to DHT. Chen et al. in a study published in 2014<ref name="pmid25320358">{{cite journal |vauthors=Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RL, Kantoff PW, Montgomery RB, Nelson PS, Bubley GJ, Balk SP, Taplin ME |title=Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors |journal=Clin Cancer Res |volume=21 |issue=6 |pages=1273–80 |date=March 2015 |pmid=25320358 |pmc=4359958 |doi=10.1158/1078-0432.CCR-14-1220 |url=}}</ref> predicted that abiraterone, a CYP17A1 inhibitor, with about 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase,<ref name="pmid28890368">{{cite journal |vauthors=de Mello Martins AGG, Allegretta G, Unteregger G, Haupenthal J, Eberhard J, Hoffmann M, van der Zee JA, Junker K, Stöckle M, Müller R, Hartmann RW, Ohlmann CH |title=CYP17A1-independent production of the neurosteroid-derived 5α-pregnan-3β,6α-diol-20-one in androgen-responsive prostate cancer cell lines under serum starvation and inhibition by Abiraterone |journal=J Steroid Biochem Mol Biol |volume=174 |issue= |pages=183–191 |date=November 2017 |pmid=28890368 |doi=10.1016/j.jsbmb.2017.09.006 |url=}}</ref><ref name="pmid28373265">{{cite journal |vauthors=Petrunak EM, Rogers SA, Aubé J, Scott EE |title=Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1 |journal=Drug Metab Dispos |volume=45 |issue=6 |pages=635–645 |date=June 2017 |pmid=28373265 |pmc=5438109 |doi=10.1124/dmd.117.075317 |url=}}</ref><ref name="pmid29710837">{{cite journal |vauthors=Fernández-Cancio M, Camats N, Flück CE, Zalewski A, Dick B, Frey BM, Monné R, Torán N, Audí L, Pandey AV |title=Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency |journal=Pharmaceuticals (Basel) |volume=11 |issue=2 |pages= |date=April 2018 |pmid=29710837 |pmc=6027421 |doi=10.3390/ph11020037 |url=}}</ref> although disrupting canonical androgen biosynthesis, while lowering levels of T, causes elevation of P4, that can be 5α-reduced hence start a backdoor pathway from P4 to DHT with roundabout of T.<ref name="pmid25320358"/> Besides that, in CRPC, 11-oxygenated androgens contribute significantly to the androgen pool.<ref name="pmid23856005"/><ref name="pmid31900912"/> 11-oxygenated androgens play a previously overlooked role in the reactivation of androgen signaling in CRPC,<ref name="pmid34520388">{{cite journal |vauthors=Ventura-Bahena A, Hernández-Pérez JG, Torres-Sánchez L, Sierra-Santoyo A, Escobar-Wilches DC, Escamilla-Núñez C, Gómez R, Rodríguez-Covarrubias F, López-González ML, Figueroa M |title=Urinary androgens excretion patterns and prostate cancer in Mexican men |journal=Endocr Relat Cancer |volume=28 |issue=12 |pages=745–756 |date=October 2021 |pmid=34520388 |doi=10.1530/ERC-21-0160 |url=}}</ref><ref name="pmid28939401">{{cite journal |title=Inefficient UGT-conjugation of adrenal 11β-hydroxyandrostenedione metabolites highlights C11-oxy C19 steroids as the predominant androgens in prostate cancer |journal=Mol Cell Endocrinol |volume=461 |issue= |pages=265–276 |pmid=28939401 |doi=10.1016/j.mce.2017.09.026|last1=Du Toit |first1=Therina |last2=Swart |first2=Amanda C. |year=2018 |s2cid=6335125 }}</ref><ref name="pmid30825506" /><ref name="pmid23856005" /><ref name="pmid31900912">{{cite journal | title = Canonical and Noncanonical Androgen Metabolism and Activity | journal = Advances in Experimental Medicine and Biology | volume = 1210 | pages = 239–277 | pmid = 31900912 | doi = 10.1007/978-3-030-32656-2_11 | isbn = 978-3-030-32655-5 | s2cid = 209748543 | last1 = Storbeck | first1 = Karl-Heinz | last2 = Mostaghel | first2 = Elahe A. | year = 2019 }}</ref><ref name="pmid23685396">{{cite journal|title=11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione |journal=J Steroid Biochem Mol Biol |volume=138 |issue= |pages=132–42 |pmid=23685396 |doi=10.1016/j.jsbmb.2013.04.010 |s2cid=3404940 |last1=Swart |first1=Amanda C. |last2=Schloms |first2=Lindie |last3=Storbeck |first3=Karl-Heinz |last4=Bloem |first4=Liezl M. |last5=Toit |first5=Therina du |last6=Quanson |first6=Jonathan L. |last7=Rainey |first7=William E. |last8=Swart |first8=Pieter |year=2013 }}</ref> because after eliminating testicular T biosynthesis by chemical or physical castration, CRPC has been shown to develop the ability to convert inactive circulating adrenal androgen precursors, DHEA and A4, to potent 11-oxygenated androgens in the 11-oxygenated pathway in addition to the 5α-dione pathway.<ref name="pmid31672619">{{cite journal |title=The role of adrenal derived androgens in castration resistant prostate cancer |journal=J Steroid Biochem Mol Biol |volume=197 |issue= |pages=105506 |year=2020 |pmid=31672619 |doi=10.1016/j.jsbmb.2019.105506|last1=Barnard |first1=Monique |last2=Mostaghel |first2=Elahe A. |last3=Auchus |first3=Richard J. |last4=Storbeck |first4=Karl-Heinz |pmc=7883395 }}</ref><ref name="pmid33974560" />In a 2021 study, Snaterse et al. demonstrated that 11KT is the most circulating active androgen in 97% of CRPC patients, accounting for 60% of the total active androgen pool. They also demonstrated that 11KT levels are not affected by castration.<ref name="pmid33974560">{{cite journal|title=11-Ketotestosterone is the predominant active androgen in prostate cancer patients after castration |journal=JCI Insight |volume=6 |issue=11 |pmid=33974560 |pmc=8262344 |doi=10.1172/jci.insight.148507 |last1=Snaterse |first1=G. |last2=Van Dessel |first2=L. F. |last3=Van Riet |first3=J. |last4=Taylor |first4=A. E. |last5=Van Der Vlugt-Daane |first5=M. |last6=Hamberg |first6=P. |last7=De Wit |first7=R. |last8=Visser |first8=J. A. |last9=Arlt |first9=W. |last10=Lolkema |first10=M. P. |last11=Hofland |first11=J. |year=2021 }}</ref> In a 2018 study by du Toit et al., the full range of androgen pathway metabolites have been shown in normal prostate and various prostate cancer cell models. 11OHA4 and 11OHT were both converted to potent androgens, 11KT and 11KDHT. Compared to T and DHT, 11-oxygenated androgens were the most predominant androgens. High levels of 11KT, 11KDHT and 11OHDHT have also been detected in prostate cancer tissue (~10–20 ng/g) and in circulation, 11KT (~200–350nM) and 11KDHT (~20nM) being the most abundant. Furthermore, glucuronidation of the 11-oxygenated androgens is hampered by the presence of an oxo- or a hydroxy- group at position 11 of androgens in prostate cancer cell models while in prostate cancer patients' plasma 11KDHT was present only in the unconjugated form, with 11KT also predominantly unconjugated.<ref name="pmid28939401"/> Ventura-Bahena et al., in a 2021 study, describing results of epidemiological studies related to androgens and prostate cancer that focused on specific androgen concentrations (such as T, A4, and DHEA) as inconsistent, hypothesized that the differences in androgen biosynthetic pathways rather than differences in specific androgen levels are associated with prostate cancer development.<ref name="pmid34520388"/> === Benign Prostatic Hyperplasia; Chronic Prostatitis/Chronic Pelvic Pain Syndrome === Androgens play a vital role in the development, growth and maintenance of the prostate.<ref name="pmid18471780" /> Therefore, the role of androgens should be seriously considered not only in CRPC, but also in clinical conditions such as BPH<ref name="pmid18471780"/> and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).<ref name="pmid18308097">{{cite journal|title=Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome |journal=Urology |volume=71 |issue=2 |pages=261–6 |pmid=18308097 |pmc=2390769 |doi=10.1016/j.urology.2007.09.025 |last1=Dimitrakov |first1=Jordan |last2=Joffe |first2=Hylton V. |last3=Soldin |first3=Steven J. |last4=Bolus |first4=Roger |last5=Buffington |first5=C.A. Tony |last6=Nickel |first6=J. Curtis |year=2008 }}</ref> The contribution of the 11-oxygenated androgens, as well as the biosynthesis of 11-oxygenated pregnanes to active androgens via a backdoor pathway, have also been demonstrated in BPH cell models showing the conversion of 11OHP4 and 11KP4 in the backdoor pathway resulting in the production of 11KDHT. Backdoor pathway intermediates were also detected in BPH tissue as well as in circulation in BPH patients.<ref name="pmid31626910">{{cite journal|title = The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 | url = | last1 = Du Toit | first1 = Therina | last2 = Swart | first2 = Amanda C. |year = 2020 }}</ref> In a paper published in 2008, Dimitrakov et al. hypothesized that CP/CPPS may be associated with a mild CYP21A2 deficiency, a cause of non-classic CAH that leads to androgen excesses.<ref name="pmid18308097"/> Non-classic CAH was generally thought to be asymptomatic in men.<ref name="pmid28582566">{{cite journal |title=Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women |journal=Hum Reprod Update |volume=23 |issue=5 |pages=580–599 |year=2017 |pmid=28582566 |doi=10.1093/humupd/dmx014 |last1=Carmina |first1=Enrico |last2=Dewailly |first2=Didier |last3=Escobar-Morreale |first3=Héctor F. |last4=Kelestimur |first4=Fahrettin |last5=Moran |first5=Carlos |last6=Oberfield |first6=Sharon |last7=Witchel |first7=Selma F. |last8=Azziz |first8=Ricardo }}</ref><ref name="pmid20671993">{{cite journal |title=Nonclassic congenital adrenal hyperplasia |journal=Int J Pediatr Endocrinol |volume=2010 |pages=625105 |year=2010 |pmid=20671993 |pmc=2910408 |doi=10.1155/2010/625105|doi-access=free |last1=Witchel |first1=Selma Feldman |last2=Azziz |first2=Ricardo }}</ref> The authors of that 2008 paper, therefore, concluded that CP/CPPS may be a consequence of a systemic condition of androgen excess but not a disease that originates in the prostate such as a localized prostate infection, inflammation, or dysfunction. We hypothesize that CYP21A2 deficiency in CP/CPPS may be associated with elevated androgens produced by pathways activated by such deficiency, i.e. backdoor pathway from P4 or 17-OHP to DHT and the pathways towards 11-oxygenated androgens. ==PubChem CIDs== In order to unambiguously define all the steroids mentioned in the present review, their respective PubChem IDs are listed below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below are intended to eliminate ambiguity caused by the use of different synonyms for the same metabolic intermediate by different authors when describing the androgen backdoor pathways. 11dF: 440707; 11K-5αdione: 11185733; 11KA4: 223997; 11KAST: 102029; 11KDHP4: 968899; 11KDHT: 11197479; 11KP4: 94166; 11KPdiol: 92264183; 11KPdione: 99568471; 11KT: 104796; 11OH-3αdiol: 349754907; 11OH-5αdione: 59087027; 11OHA4: 94141; 11OHAST: 10286365; 11OHDHP4: 11267580; 11OHDHT: 10018051; 11OHEt: 101849; 11OHP4: 101788; 11OHPdiol: 99601857; 11OHPdione: 99572627; 11OHT: 114920; 17OHP5: 3032570; 17-OHP: 6238; 17-OH-DHP: 11889565; 21dE: 102178; 21dF: 92827; 3,11diOH-DHP4: 10125849; 3α-diol: 15818; 3β-diol: 242332; 5α-DHP: 92810; 5α-dione: 222865; 5α-Pdiol: 111243; A4: 6128; A5: 10634; A5-S: 13847309; ALF: 104845; AlloP5: 92786; AST: 5879; DHEA: 5881; DHEA-S: 12594; DHT: 10635; DOC: 6166; P4: 5994; P5: 8955; T: 6013. == Abbreviations == === Steroids === * '''11dF''' 11-deoxycortisol (also known as Reichstein's substance S) * '''11K-3αdiol''' 5α-androstane-3α,17β-diol-11-one * '''11K-5αdione''' 5α-androstane-3,11,17-trione (also known as 11-ketoandrostanedione or 11-keto-5α-androstanedione) * '''11KA4''' 11-ketoandrostenedione (also known as 4-androstene-3,11,17-trione or androst-4-ene-3,11,17-trione or adrenosterone or Reichstein's substance G) * '''11KAST''' 5α-androstan-3α-ol-11,17-dione (also known as 11-ketoandrosterone) * '''11KDHP4''' 5α-pregnane-3,11,20-trione (also known as 11-ketodihydroprogesterone or allopregnanetrione) * '''11KDHT''' 11-ketodihydrotestosterone (also known as "5α-dihydro-11-keto testosterone" or 5α-dihydro-11-keto-testosterone) * '''11KP4''' 4-pregnene-3,11,20-trione (also known as pregn-4-ene-3,11,20-trione or 11-ketoprogesterone) * '''11KPdiol''' 5α-pregnane-3α,17α-diol-11,20-dione * '''11KPdione''' 5α-pregnan-17α-ol-3,11,20-trione * '''11KT''' 11-ketotestosterone (also known as 4-androsten-17β-ol-3,11-dione) * '''11OH-3αdiol''' 5α-androstane-3α,11β,17β-triol * '''11OH-5αdione''' 5α-androstan-11β-ol-3,17-dione (also known as 11β-hydroxy-5α-androstanedione) * '''11OHA4''' 11β-hydroxyandrostenedione (also known as 4-androsten-11β-ol-3,17-dione or androst-4-en-11β-ol-3,17-dione) * '''11OHAST''' 5α-androstane-3α,11β-diol-17-one (also known as 11β-hydroxyandrosterone) * '''11OHDHP4''' 5α-pregnan-11β-ol-3,20-dione (also known as 11β-hydroxydihydroprogesterone) * '''11OHDHT''' 11β-hydroxydihydrotestosterone (also known as 5α-dihydro-11β-hydroxytestosterone or 5α-androstane-11β,17β-diol-3-one or 11β,17β-dihydroxy-5α-androstan-3-one) * '''11OHEt''' 11β-hydroxyetiocholanolone (also known as 3α,11β-dihydroxy-5β-androstan-17-one) * '''11OHP4''' 4-pregnen-11β-ol-3,20-dione (also known as pregn-4-en-11β-ol-3,20-dione or 21-deoxycorticosterone or 11β-hydroxyprogesterone) * '''11OHPdiol''' 5α-pregnane-3α,11β,17α-triol-20-one * '''11OHPdione''' 5α-pregnane-11β,17α-diol-3,20-dione * '''11OHT''' 11β-hydroxytestosterone * '''17OHP5''' 17α-hydroxypregnenolone * '''17-OH-DHP''' 5α-pregnan-17α-ol-3,20-dione (also known as 17α-hydroxydihydroprogesterone) * '''17-OHP''' 17α-hydroxyprogesterone * '''21dE''' 4-pregnen-17α-ol-3,11,20-trione (also known as pregn-4-en-17α-ol-3,11,20-trione or 21-deoxycortisone) * '''21dF''' 4-pregnene-11β,17α-diol-3,20-dione (also known as 11β,17α-dihydroxyprogesterone or pregn-4-ene-11β,17α-diol-3,20-dione or 21-deoxycortisol or 21-desoxyhydrocortisone) * '''3,11diOH-DHP4''' 5α-pregnane-3α,11β-diol-20-one (also known as 3α,11β-dihydroxy-5α-pregnan-20-one) * '''3α-diol''' 5α-androstane-3α,17β-diol (also known by abbreviation "5α-Adiol" or "5α-adiol"), also known as 3α-androstanediol * '''3β-diol''' 5α-androstane-3β,17β-diol (also known as 3β-androstanediol) * '''5α-DHP''' 5α-dihydroprogesterone * '''5α-dione''' androstanedione (also known as 5α-androstane-3,17-dione) * '''5α-Pdiol''' 5α-pregnane-3α,17α-diol-20-one (also known as 17α-hydroxyallopregnanolone) * '''A4''' androstenedione (also known as 4-androstene-3,17-dione or androst-4-ene-3,17-dione) * '''A5''' androstenediol (also known as 5-androstene-3β,17β-diol or androst-5-ene-3β,17β-diol) * '''A5-S''' androstenediol sulfate * '''ALF''' 5α-pregnan-3α-ol-11,20-dione (also known, when used as a medication, as alfaxalone or alphaxalone) * '''AlloP5''' 5α-pregnan-3α-ol-20-one (also known as allopregnanolone) * '''AST''' 5α-androstan-3α-ol-17-one (also known androsterone) * '''DHEA''' dehydroepiandrosterone (also known as 3β-hydroxyandrost-5-en-17-one or androst-5-en-3β-ol-17-one) * '''DHEA-S''' dehydroepiandrosterone sulfate * '''DHT''' 5α-dihydrotestosterone (also known as 5α-androstan-17β-ol-3-one) * '''DOC''' 11-deoxycorticosterone (also known as Reichstein's substance Q) * '''P4''' progesterone * '''P5''' pregnenolone * '''T''' testosterone === Enzymes (Abbreviated by their Gene Names) === * '''AKR1C2''' aldo-keto reductase family 1 member C2 (also known as 3α-hydroxysteroid dehydrogenase type 3) * '''AKR1C3''' aldo-keto reductase family 1 member C3 (also known as 3α-hydroxysteroid dehydrogenase type 2; also known as 17β-hydroxysteroid dehydrogenase type 5 (HSD17B5)) * '''AKR1C4''' aldo-keto reductase family 1 member C4 (also known as 3α-hydroxysteroid dehydrogenase type 1) * '''CYP11A1''' cytochrome P450 cholesterol side-chain cleavage enzyme (also known by abbreviation "P450scc") * '''CYP11B1''' steroid 11β-hydroxylase * '''CYP11B2''' aldosterone synthase * '''CYP17A1''' steroid 17α-hydroxylase/17,20-lyase (also known as cytochrome P450c17) * '''CYP21A2''' steroid 21α-hydroxylase (also known as 21-hydroxylase, or cytochrome P450c21) * '''DHRS9''' dehydrogenase/reductase SDR family member 9 * '''HSD11B1''' 11β-hydroxysteroid dehydrogenase type 1 * '''HSD11B2''' 11β-hydroxysteroid dehydrogenase type 2 * '''HSD17B3''' 17β-hydroxysteroid dehydrogenase type 3 * '''HSD17B6''' 17β-hydroxysteroid dehydrogenase type 6 (also known as retinol dehydrogenase-like hydroxysteroid dehydrogenase, RL-HSD) * '''HSD17B10''' 17β-hydroxysteroid dehydrogenase type 10 * '''POR''' cytochrome P450 oxidoreductase * '''RDH16''' retinol dehydrogenase 16 (also known as RODH4) * '''RDH5''' retinol dehydrogenase 5 * '''SRD5A1''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 1 * '''SRD5A2''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 2 * '''SRD5A3''' 3-oxo-5α-steroid 4-dehydrogenase (also known as steroid 5α-reductase) type 3 === Conditions === * '''BPH''' benign prostatic hyperplasia * '''CAH''' congenital adrenal hyperplasia * '''CP/CPPS''' chronic prostatitis/chronic pelvic pain syndrome * '''CRPC''' castration-resistant prostate cancer * '''DSD''' disorder of sex development * '''PCOS''' polycystic ovary syndrome === Other === * '''ACTH''' adrenocorticotropic hormone * '''STAR''' steroidogenic acute regulatory protein == Additional Information == === Competing Interests === The authors have no competing interest. === Funding === The authors received no financial support for the research, authorship and publication of this article. === Notes on The Use of Abbreviations === The authors sometimes used "full name – abbreviation" pairs repeatedly throughout the article for easier following. === Referencing Convention === {{ordered list |When particular results or conclusions of particular research or review are discussed, it is mentioned by the year when it was published and the last name of the first author with "et al.". The year may not necessarily be mentioned close to the name. |To back up a particular claim which is an exact claim (such as which enzyme catalyzes a particular reaction), the supporting article is cited in the text as a number in square brackets from the numbered list of references, without mentioning the year and the name. The same technique is applied to support a generalization (e.g., "the prevailing dogma", "not always considered", "canonical androgen steroidogenesis") — in such case, there is a reference to one or more supporting reviews without explicitly mentioning these reviews in the text. |When multiple studies that confirm the same finding (or that are on a similar topic) are cited, they are also cited as described in p.2., i.e., giving reference numbers in square brackets and without mentioning the year and the name.}} == References == {{reflist|35em}} 2dg1esg3t0dcf664r59kv12vv33znl0 0 271287 2408228 2407898 2022-07-20T21:44:41Z Kaexer 2944801 added editorial process training wikitext text/x-wiki <noinclude>{{WikiJ top menu}}__NOTOC__ Tasks for the technical editors can be added at the bottom of the table ([https://en.wikiversity.org/wiki/WikiJournal_User_Group/Technical_editors/tasks?veaction=edit activate editing mode], click bottom row, click chevron that appears on the left, select 'insert below') Tech eds can claim tasks by adding their name to the right ([[WikiJournal User Group/Editorial guidelines/Technical editor summary|process guidelines)]] {| class="wikitable sortable" |+ !item !task !person !time taken !completion !comments |- | |editorial process training |Logan Smith |120 |2021-01-11 |Complete |- | |editorial process training |Joshua Langfus |120 |2021-01-11 |Complete |- | |editorial process training |Wilson Jacobs |120 |2021-01-11 |Complete |- | |editorial process training |Emma Choplin |120 |2021-01-11 |Complete |- | |editorial process training |Jenna Harmon |120 |2021-01-14 |Complete |- | |editorial process training |Cody Naccarato |120 |2021-01-14 |Complete |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |create/link author wikidata items |Wilson Jacobs |90 |2021-01-26 |Complete |- |[[WikiJournal of Science/Virtual colony count|Virtual colony count]] |format and upload PDF |Wilson Jacobs |150 |2021-02-13 |Complete |- |Virtual colony count |upload PDF |Wilson Jacobs |300 |2021-02-14 |Complete |- |[[WikiJournal of Science/Evolved human male preferences for female body shape|Evolved human male preferences for female body shape]] |format PDF |Jenna Harmon |150 |2021-01-21 |Complete |- |Evolved human male preferences for female body shape |upload PDF |Jenna Harmon |30 |2021-02-05 |Complete |- |[[WikiJournal of Science/Arabinogalactan-proteins|Arabinogalactan-proteins]] |format PDF and upload |Jenna Harmon |180 |2021-02-13 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |60 |2021-02-01 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |30 |2021-02-03 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-04 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-10 |Complete |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |process newly submitted article |Wilson Jacobs |150 |2021-02-09 |Complete |- |Wikidata items of each WikiJMed article ([https://w.wiki/445Z query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJSci article ([https://w.wiki/445a query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJHum article ([https://w.wiki/445b query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Authors on this list ([https://w.wiki/4fY2 query], [https://author-disambiguator.toolforge.org/work_item_oauth.php disambiguator]) |Create a wikidata item for each author and disambiguate any of their other publications on wikidata | | | | |- |[[WikiJournal of Science/Structural Model of Bacteriophage T4|Structural Model of Bacteriophage T4]] |format PDF and upload |Jenna Harmon |130 |2022-01-31 |Complete |- |[[WikiJournal of Science/A broad introduction to RNA-Seq|A broad introduction to RNA-Seq]] |format PDF and upload |Jenna Harmon |130 |2022-02-17 |Complete |- |[[WikiJournal Preprints/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |120 |2022-02-11 |Complete |- |Wikidata items of each WikiJMed author ([https://w.wiki/4463 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJSci author ([https://w.wiki/4462 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJHum author ([https://w.wiki/445q query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJMed reviewer ([https://w.wiki/445v query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJSci reviewer ([https://w.wiki/445x query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJHum reviewer ([https://w.wiki/445u query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Edit all titles to sentence case ([[Talk:WikiJournal User Group#Article title format - Why no consistency?|discussion]]) |''on hold until consensus'' Pagemove the articles, update wikidata, update the PDFs | | | | |- |Update 2021 [[WikiJournal of Medicine/Citation metrics|WikiJMed]] citation metrics |Review the number of articles published in the past 2 years (2019-2021) that cite WikiJMed articles to calculate impact factor | | | | |- |Backfill [[WikiJournal of Science/Citation metrics|citation metrics]] for WikiJSci articles from 2019-2021 |Similar to the update for WikiJMed citation metrics, this one will also need to calculate impact factors for 2019, 2020 and 2021 | | | | |- |Calculate citation metrics for WikiJHum articles from 2018-2021 |Similar to the other citation metrics tasks, this one will need to create a page from scratch for WikiJHum and calculate impact factors for 2018, 2019, 2020 and 2021 | | | | |- |[[WikiJournal Preprints/“It’s all about people skills”: Perspectives on the social license of the forest products industry from rural North America]] |Using [[:File:Soc license forestry NA Annotated text and reviewers comments - Ian Thomson.pdf|reviewer's annotated PDF]], extract the original text from the file and transfer onto the bare wiki page. |Emma Chiu |180 |2022-06-20 |Complete |- |[[WikiJournal of Medicine/History of penicillin|History of penicillin]] |format PDF and upload | | | | |- |[[WikiJournal of Medicine/Phage Therapy|Phage Therapy]] |format PDF and upload | | | | |- |[[WikiJournal of Science/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |95 |2022-05-06 |complete |- |DOAJ |upload WikiJMed and WikiJSci article metadata to DOAJ | | | | |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Parenting_stress|Parenting stress]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Leptospirosis|Leptospirosis]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Melioidosis|Melioidosis]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/A history of coronaviruses|A history of coronaviruses]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |Using [[:File:Kunu and wistar rates after review tracked changes.pdf|updated manuscript's PDF]], copy the text from the file and transfer onto the wiki page |Peter Agan | | | |- | |editorial process training 1 & 2 |Ellen Sussman |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Andrew Neil |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Natalie Charamut |120 |2022-07-11 |Complete |- |Crossref reference deposit (see [[Talk:WikiJournal User Group#Talk:WikiJournal User Group|details]]) |Submit metadata with references for published articles onto Crossref platform | | | |- | |editorial process training 1 & 2 |Emma Chiu |120 |2022-07-11 |Complete |} dsoz6vki204syf3r45l6amh6dhb0sr6 2408233 2408228 2022-07-20T23:09:02Z Evolution and evolvability 922352 + links wikitext text/x-wiki <noinclude>{{WikiJ top menu}}__NOTOC__ Tasks for the technical editors can be added at the bottom of the table ([https://en.wikiversity.org/wiki/WikiJournal_User_Group/Technical_editors/tasks?veaction=edit activate editing mode], click bottom row, click chevron that appears on the left, select 'insert below') Tech eds can claim tasks by adding their name to the right ([[WikiJournal User Group/Editorial guidelines/Technical editor summary|process guidelines)]] {| class="wikitable sortable" |+ !item !task !person !time taken !completion !comments |- | |editorial process training |Logan Smith |120 |2021-01-11 |Complete |- | |editorial process training |Joshua Langfus |120 |2021-01-11 |Complete |- | |editorial process training |Wilson Jacobs |120 |2021-01-11 |Complete |- | |editorial process training |Emma Choplin |120 |2021-01-11 |Complete |- | |editorial process training |Jenna Harmon |120 |2021-01-14 |Complete |- | |editorial process training |Cody Naccarato |120 |2021-01-14 |Complete |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |create/link author wikidata items |Wilson Jacobs |90 |2021-01-26 |Complete |- |[[WikiJournal of Science/Virtual colony count|Virtual colony count]] |format and upload PDF |Wilson Jacobs |150 |2021-02-13 |Complete |- |Virtual colony count |upload PDF |Wilson Jacobs |300 |2021-02-14 |Complete |- |[[WikiJournal of Science/Evolved human male preferences for female body shape|Evolved human male preferences for female body shape]] |format PDF |Jenna Harmon |150 |2021-01-21 |Complete |- |Evolved human male preferences for female body shape |upload PDF |Jenna Harmon |30 |2021-02-05 |Complete |- |[[WikiJournal of Science/Arabinogalactan-proteins|Arabinogalactan-proteins]] |format PDF and upload |Jenna Harmon |180 |2021-02-13 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |60 |2021-02-01 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |30 |2021-02-03 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-04 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-10 |Complete |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |process newly submitted article |Wilson Jacobs |150 |2021-02-09 |Complete |- |Wikidata items of each WikiJMed article ([https://w.wiki/445Z query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJSci article ([https://w.wiki/445a query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJHum article ([https://w.wiki/445b query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Authors on this list ([https://w.wiki/4fY2 query], [https://author-disambiguator.toolforge.org/work_item_oauth.php disambiguator]) |Create a wikidata item for each author and disambiguate any of their other publications on wikidata | | | | |- |[[WikiJournal of Science/Structural Model of Bacteriophage T4|Structural Model of Bacteriophage T4]] |format PDF and upload |Jenna Harmon |130 |2022-01-31 |Complete |- |[[WikiJournal of Science/A broad introduction to RNA-Seq|A broad introduction to RNA-Seq]] |format PDF and upload |Jenna Harmon |130 |2022-02-17 |Complete |- |[[WikiJournal Preprints/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |120 |2022-02-11 |Complete |- |Wikidata items of each WikiJMed author ([https://w.wiki/4463 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJSci author ([https://w.wiki/4462 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJHum author ([https://w.wiki/445q query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJMed reviewer ([https://w.wiki/445v query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJSci reviewer ([https://w.wiki/445x query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJHum reviewer ([https://w.wiki/445u query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Edit all titles to sentence case ([[Talk:WikiJournal User Group#Article title format - Why no consistency?|discussion]]) |''on hold until consensus'' Pagemove the articles, update wikidata, update the PDFs | | | | |- |Update 2021 [[WikiJournal of Medicine/Citation metrics|WikiJMed]] citation metrics |Review the number of articles published in the past 2 years (2019-2021) that cite WikiJMed articles to calculate impact factor | | | | |- |Backfill [[WikiJournal of Science/Citation metrics|citation metrics]] for WikiJSci articles from 2019-2021 |Similar to the update for WikiJMed citation metrics, this one will also need to calculate impact factors for 2019, 2020 and 2021 | | | | |- |Calculate citation metrics for WikiJHum articles from 2018-2021 |Similar to the other citation metrics tasks, this one will need to create a page from scratch for WikiJHum and calculate impact factors for 2018, 2019, 2020 and 2021 | | | | |- |[[WikiJournal Preprints/“It’s all about people skills”: Perspectives on the social license of the forest products industry from rural North America]] |Using [[:File:Soc license forestry NA Annotated text and reviewers comments - Ian Thomson.pdf|reviewer's annotated PDF]], extract the original text from the file and transfer onto the bare wiki page. |Emma Chiu |180 |2022-06-20 |Complete |- |[[WikiJournal of Medicine/History of penicillin|History of penicillin]] |format PDF and upload | | | | |- |[[WikiJournal of Medicine/Phage Therapy|Phage Therapy]] |format PDF and upload | | | | |- |[[WikiJournal of Science/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |95 |2022-05-06 |complete |- |[[WikiJournal User Group/Editorial guidelines#Registering article in DOAJ|DOAJ]] |upload WikiJMed and WikiJSci [[WikiJournal User Group/Editorial guidelines#Registering article in DOAJ|article metadata to DOAJ]] | | | | |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Parenting_stress|Parenting stress]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Leptospirosis|Leptospirosis]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Melioidosis|Melioidosis]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/A history of coronaviruses|A history of coronaviruses]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |Using [[:File:Kunu and wistar rates after review tracked changes.pdf|updated manuscript's PDF]], copy the text from the file and transfer onto the wiki page |Peter Agan | | | |- |Crossref reference deposit (see [[Talk:WikiJournal User Group#Talk:WikiJournal User Group|details]]) |[[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|Submit metadata with references for published articles onto Crossref platform]] | | | |- | |editorial process training 1 & 2 |Ellen Sussman |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Andrew Neil |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Natalie Charamut |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Emma Chiu |120 |2022-07-11 |Complete |} ppkjlc6l8j8z1j33ecyhl37dp1jbgp9 2408235 2408233 2022-07-20T23:11:32Z Evolution and evolvability 922352 ce wikitext text/x-wiki <noinclude>{{WikiJ top menu}}__NOTOC__ Tasks for the technical editors can be added at the bottom of the table ([https://en.wikiversity.org/wiki/WikiJournal_User_Group/Technical_editors/tasks?veaction=edit activate editing mode], click bottom row, click chevron that appears on the left, select 'insert below') Tech eds can claim tasks by adding their name to the right ([[WikiJournal User Group/Editorial guidelines/Technical editor summary|process guidelines)]] {| class="wikitable sortable" |+ !item !task !person !time taken !completion !comments |- | |editorial process training |Logan Smith |120 |2021-01-11 |Complete |- | |editorial process training |Joshua Langfus |120 |2021-01-11 |Complete |- | |editorial process training |Wilson Jacobs |120 |2021-01-11 |Complete |- | |editorial process training |Emma Choplin |120 |2021-01-11 |Complete |- | |editorial process training |Jenna Harmon |120 |2021-01-14 |Complete |- | |editorial process training |Cody Naccarato |120 |2021-01-14 |Complete |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |create/link author wikidata items |Wilson Jacobs |90 |2021-01-26 |Complete |- |[[WikiJournal of Science/Virtual colony count|Virtual colony count]] |format and upload PDF |Wilson Jacobs |150 |2021-02-13 |Complete |- |Virtual colony count |upload PDF |Wilson Jacobs |300 |2021-02-14 |Complete |- |[[WikiJournal of Science/Evolved human male preferences for female body shape|Evolved human male preferences for female body shape]] |format PDF |Jenna Harmon |150 |2021-01-21 |Complete |- |Evolved human male preferences for female body shape |upload PDF |Jenna Harmon |30 |2021-02-05 |Complete |- |[[WikiJournal of Science/Arabinogalactan-proteins|Arabinogalactan-proteins]] |format PDF and upload |Jenna Harmon |180 |2021-02-13 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |60 |2021-02-01 |Complete |- |[[WikiJournal Preprints/Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol|Does the packaging of health information affect the assessment of its reliability? A randomized controlled trial protocol]] |peer-review processing |Logan Smith |30 |2021-02-03 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-04 |Complete |- |[[WikiJournal Preprints/Affine symmetric group|Affine symmetric group]] |peer-review processing |Logan Smith |30 |2021-02-10 |Complete |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |process newly submitted article |Wilson Jacobs |150 |2021-02-09 |Complete |- |Wikidata items of each WikiJMed article ([https://w.wiki/445Z query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJSci article ([https://w.wiki/445a query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Wikidata items of each WikiJHum article ([https://w.wiki/445b query]; [[wikidata:Q96317242#P50|example]]) |add email address to corresponding author | | | | |- |Authors on this list ([https://w.wiki/4fY2 query], [https://author-disambiguator.toolforge.org/work_item_oauth.php disambiguator]) |Create a wikidata item for each author and disambiguate any of their other publications on wikidata | | | | |- |[[WikiJournal of Science/Structural Model of Bacteriophage T4|Structural Model of Bacteriophage T4]] |format PDF and upload |Jenna Harmon |130 |2022-01-31 |Complete |- |[[WikiJournal of Science/A broad introduction to RNA-Seq|A broad introduction to RNA-Seq]] |format PDF and upload |Jenna Harmon |130 |2022-02-17 |Complete |- |[[WikiJournal Preprints/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |120 |2022-02-11 |Complete |- |Wikidata items of each WikiJMed author ([https://w.wiki/4463 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJSci author ([https://w.wiki/4462 query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJHum author ([https://w.wiki/445q query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all authors | | | | |- |Wikidata items of each WikiJMed reviewer ([https://w.wiki/445v query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJSci reviewer ([https://w.wiki/445x query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Wikidata items of each WikiJHum reviewer ([https://w.wiki/445u query]) |add [[wikidata:Property:P101|fields of work]], employers, orcid, and official website for all peer reviewers | | | | |- |Edit all titles to sentence case ([[Talk:WikiJournal User Group#Article title format - Why no consistency?|discussion]]) |''on hold until consensus'' Pagemove the articles, update wikidata, update the PDFs | | | | |- |Update 2021 [[WikiJournal of Medicine/Citation metrics|WikiJMed]] citation metrics |Review the number of articles published in the past 2 years (2019-2021) that cite WikiJMed articles to calculate impact factor | | | | |- |Backfill [[WikiJournal of Science/Citation metrics|citation metrics]] for WikiJSci articles from 2019-2021 |Similar to the update for WikiJMed citation metrics, this one will also need to calculate impact factors for 2019, 2020 and 2021 | | | | |- |Calculate citation metrics for WikiJHum articles from 2018-2021 |Similar to the other citation metrics tasks, this one will need to create a page from scratch for WikiJHum and calculate impact factors for 2018, 2019, 2020 and 2021 | | | | |- |[[WikiJournal Preprints/“It’s all about people skills”: Perspectives on the social license of the forest products industry from rural North America]] |Using [[:File:Soc license forestry NA Annotated text and reviewers comments - Ian Thomson.pdf|reviewer's annotated PDF]], extract the original text from the file and transfer onto the bare wiki page. |Emma Chiu |180 |2022-06-20 |Complete |- |[[WikiJournal of Medicine/History of penicillin|History of penicillin]] |format PDF and upload | | | | |- |[[WikiJournal of Medicine/Phage Therapy|Phage Therapy]] |format PDF and upload | | | | |- |[[WikiJournal of Science/“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics|“Collect, acquire, analyze, report, and disseminate statistical data related to the science and engineering enterprise…”: The National Center for Science and Engineering Statistics]] |format PDF and upload |Jenna Harmon |95 |2022-05-06 |complete |- |[[WikiJournal User Group/Editorial guidelines#Registering article in DOAJ|DOAJ]] |upload WikiJMed and WikiJSci [[WikiJournal User Group/Editorial guidelines#Registering article in DOAJ|article metadata to DOAJ]] | | | | |- |[[WikiJournal Preprints/The Kivu Ebola epidemic|Kivu Ebola epidemic]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Parenting_stress|Parenting stress]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Leptospirosis|Leptospirosis]] |format PDF and upload | | | | |- |[[WikiJournal Preprints/Melioidosis|Melioidosis]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/A history of coronaviruses|A history of coronaviruses]] |Almost ready - awaiting final references - no action yet | | | | |- |[[WikiJournal Preprints/The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats|The effect of local millet drink (Kunu) on the testis and epididymis of adult male wistar rats]] |Using [[:File:Kunu and wistar rates after review tracked changes.pdf|updated manuscript's PDF]], copy the text from the file and transfer onto the wiki page |Peter Agan | | | |- |Crossref reference deposit (see [[Talk:WikiJournal User Group#Talk:WikiJournal User Group|discussion]]) |[[WikiJournal User Group/Editorial guidelines#Submitting reference metadata|Submit metadata with references for published articles onto Crossref platform]] | | | |- | |editorial process training 1 & 2 |Ellen Sussman |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Andrew Neil |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Natalie Charamut |120 |2022-07-11 |Complete |- | |editorial process training 1 & 2 |Emma Chiu |120 |2022-07-11 |Complete |} 8pt07umkz45kf7l4zzg0f5cqvv5pfv3 0 277657 2408269 2407002 2022-07-21T04:23:28Z Hanarose123 2946863 /* Motivation */ wikitext text/x-wiki {{/Banner}} ==Motivation== # [[/Academic help-seeking/]] - What are the barriers and enablers of AHS and how can AHS be fostered? - [[User:MyUserName|MyUserName]] # [[/Academic self-regulation/]] - What is academic self-regulation, why does it matter, and how can it be fostered? - [[User:MyUserName|MyUserName]] # [[/Actively open-minded thinking/]] - How can AOT be used to improve human performance? - [[User:MyUserName|MyUserName]] # [[/Active transport motivation/]] - What motivates use of active transport and how can people be encouraged to use it? - [[User:MyUserName|MyUserName]] # [[/Antidepressants and motivation/]] - What are the effects of popular antidepressants on motivation? - [[User:MyUserName|MyUserName]] # [[/Approach motivation/]] - What is approach motivation and how does it lead to behaviour? - [[User:U3189370|U3189370]] # [[/Behavioural economics and motivation/]] - What aspects of motivation theory are useful in behavioural economics? - [[User:MyUserName|MyUserName]] # [[/Behavioural model of health services/]] - What is the BMHS and how can it be used? - [[User:MyUserName|MyUserName]] # [[/Beneficence as a psychological need/]] - What is beneficence and what are its implications as a psychological need? - [[User:MyUserName|MyUserName]] # [[/Brief motivational interviewing as a health intervention/]] - How can brief motivational interviewing be used as a health intervention? - [[User:MyUserName|MyUserName]] # [[/Choice overload/]] - How much choose is too much? How much choice is enough? - [[User:MyUserName|MyUserName]] # [[/Chunking and goal pursuit/]] - How does chunking affect goal pursuit? - [[User:MyUserName|MyUserName]] # [[/Cognitive entrenchment/]] - What is cognitive entrenchment and how can it be avoided? - [[User:MyUserName|MyUserName]] # [[/Climate change helplessness/]] - How does learned helpless impact motivation to engage in behaviours to limit climate change? - [[User:MyUserName|MyUserName]] # [[/Closeness communication bias/]] - What is the CCB, why does it occur, and how can it be overcome? - [[User:MyUserName|MyUserName]] # [[/Commitment bias/]] - What motivates escalation of commitment even it does not lead to desirably outcomes? - [[User:MyUserName|MyUserName]] # [[/Conspiracy theory motivation/]] - What motivates people to believe in conspiracy theories? - [[User:MyUserName|MyUserName]] # [[/Construal level theory/]] - What is construal level theory and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Courage motivation/]] - What is courage, what motivates courage, and how can courage be enhanced? -[[User:U3213871] # [[/Death drive/]] - What is the death drive and how can it be negotiated? - [[User:MyUserName|MyUserName]] # [[/Drugs-violence nexus and motivation/]] - What is the role of motivation in the drugs-violence nexus? - [[User:MyUserName|MyUserName]] # [[/Episodic future thinking and delay discounting/]] - What is the relationship between between EFT and DD? - [[User:MyUserName|MyUserName]] # [[/Episodic memory and planning/]] - What role does episodic memory play in planning? - [[User:MyUserName|MyUserName]] # [[/Equity theory/]] - What is equity theory and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Frame of reference and motivation/]] - How does frame of reference affect motivation? - [[User:MyUserName|MyUserName]] # [[/Freedom and motivation/]] - What is the effect of freedom on motivation? - [[User:MyUserName|MyUserName]] # [[/Fully functioning person/]] - What is a FFP and how can full functioning be developed? - [[User:MyUserName|MyUserName]] # [[/Functional fixedness/]] - What is functional fixedness and how can it be overcome? - [[User:MyUserName|MyUserName]] # [[/Functional imagery training/]] - What is FIT and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Gamification and work motivation/]] - How can gamification enhance work motivation? - [[User:MyUserName|MyUserName]] # [[/Giving up goals/]] - When should we give up goals and when should we persist? - [[User:MyUserName|MyUserName]] # [[/Green prescription motivation/]] - What motivates green prescription compliance? - [[User:MyUserName|MyUserName]] # [[/Health belief model/]] - What is the HBM and how can it be used to enhance motivation for health-promoting behaviour? - [[User:MyUserName|MyUserName]] # [[/Hijack hypothesis of drug addiction/]] - What is the hijack hypothesis, what is the evidence, and how does it help to understand drug addiction? - [[User:MyUserName|MyUserName]] # [[/Honesty motivation/]] - What motivates honesty? - [[User:MyUserName|MyUserName]] # [[/Humour and work/]] - What is the role of humour in the workplace? - [[User:MyUserName|MyUserName]] # [[/IKEA effect/]] - What is the IKEA effect and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Intertemporal choice/]] - What are intertemporal choices and how can they be effectively negotiated? - [[User:MyUserName|MyUserName]] # [[/Kindness motivation/]] - What motivates kindness? - [[User:MyUserName|MyUserName]] # [[/Motivational music and exercise/]] - How can music be used to help motivate exercise? - [[User:MyUserName|MyUserName]] # [[/Novelty-variety as a psychological need/]] - What is novelty-variety and what are its implications as a psychological need? - [[User:MyUserName|MyUserName]] # [[/Nucleus accumbens and motivation/]] - What role does the nucleus accumbens play in motivation? - [[User:MyUserName|MyUserName]] # [[/Physiological needs/]] - What are human's physiological needs and how does this influence motivation? - [[User:MyUserName|MyUserName]] # [[/Protection motivation theory and COVID-19/]] - How does PMT apply to managing COVID-19? - [[User:MyUserName|MyUserName]] # [[/Relative deprivation and motivation/]] - What is the effect of relative deprivation on motivation? - [[User:MyUserName|MyUserName]] # [[/Retrospective regret/]] - What is the motivational role of retrospective regret? - [[User:MyUserName|MyUserName]] # [[/Revenge motivation/]] - What motivates revenge and how does it affect us? - [[User:MyUserName|MyUserName]] # [[/Self-efficacy and achievement/]] - What role does self-efficacy play in achievement outcomes? - [[User:U943292|U943292]] # [[/Sexual harassment at work motivation/]] - What motivates sexual harassment at work and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Signature strengths/]] - What are signature strengths and how can they be applied? - [[User:MyUserName|MyUserName]] # [[/Social cure/]] - What is the social cure and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/System justification theory/]] - What is SJT, how does it affect our lives, and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Stretch goals/]] - What are stretch goals? Do they work? - [[User:MyUserName|MyUserName]] # [[/Sublimation/]] - What is sublimation and how can it be fostered? - [[User:MyUserName|MyUserName]] # [[/Survival needs and motivation/]] - What are survival needs and how do they influence motivation? - [[User:MyUserName|MyUserName]] # [[/Task initiation/]] - What are the challenges with task initiation and how to get get started? - [[User:MyUserName|MyUserName]] # [[/Theoretical domains framework/]] - What is the TDF and how can be used to guide behaviour change? - [[User:MyUserName|MyUserName]] # [[/Time and motivation/]] - What is the effect of time on motivation? - [[User:MyUserName|MyUserName]] # [[/Time management/]] - How can one's time be managed effectively? - [[User:MyUserName|MyUserName]] # [[/To-do lists/]] - Are to-do lists a good idea? What are their pros and cons? How can they be used effectively? - [[User:MyUserName|MyUserName]] # [[/Uncertainty avoidance/]] - What is uncertainty avoidance, why does it occur, and what are its consequences? - [[User:MyUserName|MyUserName]] # [[/Urgency bias and productivity/]] - What is the impact of urgency bias on productivity and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Vocational identity/]] - What is vocational identity and how does it develop? - [[User:MyUserName|MyUserName]] # [[/Wanting and liking/]] - What are the similarities and differences between wanting and liking, and what are the implications? - [[User:MyUserName|MyUserName]] # [[/Work breaks, well-being, and productivity/]] - How do work breaks affect well-being and productivity? - [[User:MyUserName|MyUserName]] # [[/Work and flow/]] - What characteristics of work can produce flow and how can flow at work be fostered? - [[User:MyUserName|MyUserName]] ==Emotion== # [[/Animal emotion/]] - What is the emotional experience of animals? - [[User:MyUserName|MyUserName]] # [[/Attributions and emotion/]] - How do attributions affect emotion? - [[User:MyUserName|MyUserName]] # [[/Autonomous sensory meridian response and emotion/]] - What emotions are involved in ASMR experiences and why do they occur? - [[User:MyUserName|MyUserName]] # [[/Benzodiazepines and emotion/]] - What are the effects of benzodiazepines on emotion? - [[User:MyUserName|MyUserName]] # [[/Bewilderment/]] - What is bewilderment and how can it be dealt with? - [[User:MyUserName|MyUserName]] # [[/Burnout/]] - What is burnout and how can be it be managed and prevented? - [[User:MyUserName|MyUserName]] # [[/Cognitive dissonance reduction/]] - What strategies do people use to reduce cognitive dissonance and how effective are they? - [[User:MyUserName|MyUserName]] # [[/Colonisation and emotion in Australia/]] - What are the emotional responses to colonisation in Australia? - [[User:MyUserName|MyUserName]] # [[/Compassion/]] - What is compassion, what are its pros and cons, and how can it be fostered? - [[User:MyUserName|MyUserName]] # [[/Connection to country and well-being/]] - What is the relationship between connection to country and well-being? - [[User:MyUserName|MyUserName]] # [[/Contempt/]] - What is contempt, what causes it, and how can it be managed? - [[User:MyUserName|MyUserName]] # [[/Core emotions/]] - What are the core emotions and what is their function? - [[User:MyUserName|MyUserName]] # [[/Creative arts and trauma/]] - How can creative arts help in dealing with trauma? - [[User:MyUserName|MyUserName]] # [[/Cultural influences on shame, guilt, and pride/]] - How does culture influence shame, guilt, and pride? - [[User:MyUserName|MyUserName]] # [[/Default mode network and the self/]] - What is the relationship between the DMN and the self? - [[User:MyUserName|MyUserName]] # [[/Difficult conversations and emotion/]] - What communication and emotional skills are needed to successfully negotiate difficult conversations? - [[User:MyUserName|MyUserName]] # [[/Disappointment/]] - What is disappointment, what causes it, and how can it be managed? - [[User:MyUserName|MyUserName]] # [[/DMT and spirituality/]] - How can DMT facilitate spiritual experiences? - [[User:MyUserName|MyUserName]] # [[/Durability bias in affective forecasting/]] - What role does durability bias play in affective forecasting? - [[User:MyUserName|MyUserName]] # [[/Ecological grief/]] - What is ecological grief and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Embarrassment/]] - What is embarrassment, what causes it, and how can it be managed? - [[User:MyUserName|MyUserName]] # [[/Emotional intelligence training/]] - How can emotional intelligence be trained? - [[User:MyUserName|MyUserName]] # [[/Emotion knowledge/]] - What is emotion knowledge and how can it be developed? - [[User:MyUserName|MyUserName]] # [[/Emotion across the lifespan/]] - How does emotion develop across the lifespan? - [[User:MyUserName|MyUserName]] # [[/Endocannabinoid system and emotion/]] - What is the role of the endocannabinoid system in emotion? - [[User:MyUserName|MyUserName]] # [[/Environmental grief/]] - What is eco-grief, its causes and consequences, and what can be done? - [[User:MyUserName|MyUserName]] # [[/Exercise and endocannabinoids/]] - What is the relationship between exercise and the endocannabinoid system? - [[User:MyUserName|MyUserName]] # [[/Expressive suppression and emotion regulation/]] - What is the role of expressive suppression in emotion regulation? - [[User:MyUserName|MyUserName]] # [[/Fairness and emotion/]] - What is the relation between fairness and emotion? - [[User:MyUserName|MyUserName]] # [[/Fatigue and emotion/]] - What is the effect of fatigue on emotion and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Fear/]] - What is fear, what causes it, and how can it be managed? - [[User:MyUserName|MyUserName]] # [[/Fear of working out/]] - What is FOWO and how can it be overcome? - [[User:MyUserName|MyUserName]] # [[/Fundamental attribution error and emotion/]] - What is the relationship between the FAE and emotion? - [[User:MyUserName|MyUserName]] # [[/Gloatrage/]] - What is gloatrage, what causes it, and what are its consequences? - [[User:MyUserName|MyUserName]] # [[/Heart rate variability and emotion regulation/]] - What is the relationship between HRV and emotion regulation? - [[User:MyUserName|MyUserName]] # [[/Hedonic adaptation prevention model/]] - What is the HAP model and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Humility/]] - What is humility, what causes it, and is it desirable? - [[User:MyUserName|MyUserName]] # [[/Hypomania and emotion/]] - What are the emotional characteristics of hypomania? - [[User:MyUserName|MyUserName]] # [[/Impact bias/]] - What is impact bias, what causes it, what are its consequences, and how can it be avoided? - [[User:MyUserName|MyUserName]] # [[Indigenous Australian emotionality]] - In what ways is emotionality experienced by Indigenous Australian people? - [[User:MyUserName|MyUserName]] # [[/Indigenous Australian mindfulness/]] - How has Indigenous Australian culture traditionally conceived of, and practiced, mindfulness? - [[User:MyUserName|MyUserName]] # [[/Inspiration/]] - What is inspiration, what causes it, what are its consequences, and how can it be fostered? - [[User:MyUserName|MyUserName]] # [[/Insular cortex and emotion/]] - What role does the insular cortex play in emotion? - [[User:MyUserName|MyUserName]] # [[/Interoception and emotion/]] - What is the relationship between interoception and emotion? - [[User:MyUserName|MyUserName]] # [[/Kama muta/]] - What is kama muta, what are its effects, and how can it be fostered? - [[User:MyUserName|MyUserName]] # [[/Linguistic relativism and emotion/]] - What is the role of linguistic relativism in emotion? - [[User:MyUserName|MyUserName]] # [[/Menstrual cycle mood disorders/]] - What causes menstrual cycle mood disorders and how can they be managed? - [[User:MyUserName|MyUserName]] # [[/Mindfulness and creativity/]] - How can mindfulness enhance creativity? - [[User:MyUserName|MyUserName]] # [[/Mindfulness and driving/]] - How can mindfulness affect driving? - [[User:MyUserName|MyUserName]] # [[/Mindful self-care/]] - What is mindful self-care, why does it matter, and how can it be developed? - [[User:MyUserName|MyUserName]] # [[/Mixed emotions/]] - What are mixed emotions, what causes them, and how can they be managed? - [[User:MyUserName|MyUserName]] # [[/Mudita/]] - What is mudita and how can it be developed? - [[User:MyUserName|MyUserName]] # [[/Natural disasters and emotion/]] - How do people respond emotionally to natural disasters and how can they be supported? - [[User:MyUserName|MyUserName]] # [[/Nature therapy/]] - What is nature therapy and how can it be applied? - [[User:MyUserName|MyUserName]] # [[/Narcissism and emotion/]] - What is the relationship between narcissism and emotion? - [[User:MyUserName|MyUserName]] # [[/Narrative therapy and emotion/]] - What is the role of emotion in narrative therapy? - [[User:MyUserName|MyUserName]] # [[/Needle fear/]] - How does needle fear develop, what are its consequences, and what can be done about it? - [[User:MyUserName|MyUserName]] # [[/Positivity ratio/]] - What is the positivity ratio and what are its implications? - [[User:MyUserName|MyUserName]] # [[/Post-traumatic stress disorder and emotion/]] - What is the effect of PTSD on emotion? - [[User:JorjaFive|U822459]] # [[/Psychological distress/]] - What is PD, what are the main types, and how can they be managed? - [[User:MyUserName|MyUserName]] # [[/Psychological trauma/]] - What causes psychological trauma, what are the consequences, and how can people recover from psychological trauma? - [[User:MyUserName|MyUserName]] # [[/Rational compassion/]] - What is rational compassion and how can it be cultivated? - [[User:MyUserName|MyUserName]] # [[/Reflected glory/]] - What is reflected glory and what are its pros and cons? - [[User:MyUserName|MyUserName]] # [[/Religiosity and coping/]] - What is the relationship between religiosity and coping? - [[User:MyUserName|MyUserName]] # [[/Resentment/]] - What is resentment, what causes it, and what are its consequences? - [[User:MyUserName|MyUserName]] # [[/Risk-as-feelings/]] - What is the emotional experience of risk and how does it influence decision-making and behaviour? - [[User:MyUserName|MyUserName]] # [[/Self-esteem and culture/]] - What are the cultural influences on self-esteem? - [[User:MyUserName|MyUserName]] # [[/Smiling and emotion/]] - What is the relationship between smiling and emotion? - [[User:MyUserName|MyUserName]] # [[/Social media and suicide prevention/]] - How can social media be used to help prevent suicide? - [[User:MyUserName|MyUserName]] # [[/Sorry business/]] - What is sorry business and what role does it play in Indigenous communities in Australia? - [[User:MyUserName|MyUserName]] # [[/Stress control mindset/]] - What is a SCM, why does it matter, and how can it be cultivated? - [[User:MyUserName|MyUserName]] # [[/Suffering as emotion/]] - What is the emotional experience of suffering and how can people cope with suffering? - [[User:MyUserName|MyUserName]] # [[/Telemental health/]] - What are the pros and cons of TMH and what are the key ingredients for effective TMH practices? - [[User:MyUserName|MyUserName]] # [[/Topophilia/]] - What is topophilia, how does it develop, and what are the psychological impacts? - [[User:MyUserName|MyUserName]] # [[/Triumph/]] - What is triumph, what causes it, and how can it be managed? - [[User:MyUserName|MyUserName]] # [[/Unemployment and mental health/]]: What is the relationship between unemployment and mental health? - [[User:MyUserName|MyUserName]] # [[/Viewing natural scenes and emotion/]] - What is the effect of viewing natural scenes on emotion and how can this be applied? - [[User:MyUserName|MyUserName]] # [[/Volunteer tourism motivation/]] - What motivates volunteer tourism? - [[User:Efost|MyUserName]] # [[/Wave metaphor for emotion/]] - In what respects is an ocean wave a helpful metaphor for understanding human emotions? - [[User:MyUserName|MyUserName]] # [[/Window of tolerance/]] - What is the window of tolerance and how this concept be used? - [[User:MyUserName|MyUserName]] # [[/Workplace mental health training/]] - What is WMHT, what techniques are used, and what are the impacts? - [[User:MyUserName|MyUserName]] # [[/Zoom fatigue/]] - What is Zoom fatigue, what causes it, what are its consequences, and what can be done about it? - [[User:MyUserName|MyUserName]] ==Motivation and emotion== # [[/Financial investing, motivation, and emotion/]] - What role does motivation and emotion play in financial investing? - [[User:MyUserName|MyUserName]] # [[/Hostage negotiation, motivation, and emotion/]] - What role does motivation and emotion play in hostage negotiation? - [[User:U3213549|U3213549]] # [[/Money priming, motivation, and emotion/]] - What is the effect of money priming on motivation and emotion? - [[User:MyUserName|MyUserName]] # [[/Motivational dimensional model of affect/]] - What is the motivational dimensional model of affect and what are its implications? - [[User:MyUserName|MyUserName]] # [[/Napping, motivation, and emotion/]] - What are the motivational and emotional effects of napping? - [[User:MyUserName|MyUserName]] # [[/Overchoice, emotion, and motivation/]] - What are the emotional and motivational effects of overchoice? - [[User:MyUserName|MyUserName]] # [[/Patience and impatience/]] - What are the psychological causes and consequences of patience and impatience? - [[User:MyUserName|MyUserName]] # [[/Reward system, motivation, and emotion/]] - What role does the reward system play in motivation and emotion? - [[User:MyUserName|MyUserName]] [[Category:Motivation and emotion/Book/2022]] dzwdrjkkaycmr79dcajcbixwtogqmyn 2 277685 2408249 2406428 2022-07-21T01:44:52Z Jtwsaddress42 234843 wikitext text/x-wiki {{User:Jtwsaddress42/Bibliography}} '''[[User:Jtwsaddress42/People_A|<big>A</big>]]''' {{RoundBoxTop|theme=2}} * {{cite book | last= Abbott | first= Edwin A. | year= 1884 | title= Flatland: A Romance of Many Dimensions | publication= Dover Publications | publication-date= 1952 | isbn= 978-1-434-45099-9 | url= https://store.doverpublications.com/048627263x.html }} * {{cite journal | last1= Abed, Riadh T. | year= 2000 | title= Psychiatry and Darwinism: Time to Reconsider? | journal= The British Journal of Psychiatry | volume= 177 | number= 1 | pages= 1-3 | publication-date= July 2000 | pmid= 10945079 | doi= 10.1192/bjp.177.1.1 | url=https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/psychiatry-and-darwinism/7BD5D340A5733904C41868BCBEEBB74C }} * {{cite book | last= Abir-Am | first= P.G. | year= 1994 | chapter= The Philosphical Background of Joseph Needham&acute;s Work in Chemical Embryology | title= A Conceptual History of Modern Embryology | pages= 159-180 | volume= 7 | editor= Scott F. 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H.B.M. | year= 1998 | title= The Functions of the Preplate in Development and Evolution of the Neocortex and Hippocampus | journal= Brain Research Reviews | volume= 27 | number= 1 | pages= 40-64 | publication-date= June 1998 | pmid= 9639671 | doi= 10.1016/s0165-0173(98)00005-8 | url= https://www.sciencedirect.com/science/article/abs/pii/S0165017398000058?via%3Dihub }} * {{cite journal | last1= Super | first1= H. | last2= Uylings | first2= H.B.M. | year= 2001 | title= The Early Differentiation of the Neocortex: a Hypothesis on Neocortical Evolution | journal= Cerebral Cortex | volume= 11 | number= 12 | pages= 1101-1109 | publication-date= December 1, 2001 | pmid= 11709481 | doi= 10.1093/cercor/11.12.1101 | url= https://academic.oup.com/cercor/article/11/12/1101/492309 }} {{User:Jtwsaddress42/Bibliography/Suzuki, Akira}} * {{cite journal | last1= Swalla | first1= Billie J. | last2= Jeffery | first2= William R. | year= 1996 | title= Requirement of the Manx Gene for Expression of Chordate 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Synder | first= Alison | year= 2014 | title=Obiturary: Gerald Edelman | journal= The Lancet | volume= 383 | number= 9936 | pages= P2206 | publication-date= June 28, 2014 | doi= 10.1016/S0140-6736(14)61075-8 | url= https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61075-8/fulltext#%20}} * {{cite journal | last= Szathmary | first= Eors | year= 1993 | title= Coding Coenzyme Handles: A Hypothesis for the Origin of the Genetic Code | journal= Proceedings of the National Academy of Sciences, USA | volume= 90 | number= 21 | pages= 9916-9920 | publication-date= November 1993 | pmid= 8234335 | pmc= 47683 | doi= 10.1073/pnas.90.21.9916 | url= https://www.pnas.org/content/90/21/9916 }} {{User:Jtwsaddress42/Bibliography/Szoke, Abraham}} {{User:Jtwsaddress42/Bibliography/Szostak, Jack}} {{RoundBoxBottom}} {{User:Jtwsaddress42/Includes/Notes_&_Citations}} {{User:Jtwsaddress42/Navigation/Footer Navbar}} {{User:Jtwsaddress42/Includes/Categories}} 87vj2cmhisiuv27gtgwt79ey4dlmkfh 2 277734 2408280 2406894 2022-07-21T04:55:56Z Jtwsaddress42 234843 wikitext text/x-wiki {{User:Jtwsaddress42/People}} '''[[User:Jtwsaddress42/Bibliography_C|<big>C</big>]]''' {{User:Jtwsaddress42/People/Calvin,_William_H.}} {{User:Jtwsaddress42/People/Carlsson, Arvid}} {{User:Jtwsaddress42/People/Cavalier-Smith,_Thomas}} {{User:Jtwsaddress42/People/Changeux,_Jean-Pierre}} {{User:Jtwsaddress42/People/Chomsky, Noam}} {{User:Jtwsaddress42/People/Cisek,_Paul}} {{User:Jtwsaddress42/Includes/Notes_&_Citations}} {{User:Jtwsaddress42/Navigation/Footer Navbar}} labjhvv4jtm7yoj85v067l5pvdmrwmd 2 277744 2408259 2407267 2022-07-21T03:53:48Z Jtwsaddress42 234843 wikitext text/x-wiki {{User:Jtwsaddress42/People}} '''[[User:Jtwsaddress42/Bibliography_M|<big>M</big>]]''' {{User:Jtwsaddress42/People/Mackie, George O.}} {{User:Jtwsaddress42/People/Metchnikoff,_Élie}} {{User:Jtwsaddress42/People/Millhauser, Glenn}} {{User:Jtwsaddress42/People/Morris, Simon Conway}} {{User:Jtwsaddress42/Includes/Notes_&_Citations}} {{User:Jtwsaddress42/Navigation/Footer Navbar}} e6n3164bbl3esg6ji9e1zacwqsqajtf 2 277745 2408270 2407461 2022-07-21T04:25:03Z Jtwsaddress42 234843 wikitext text/x-wiki {{User:Jtwsaddress42/People}} '''[[User:Jtwsaddress42/Bibliography_N|<big>N</big>]]''' {{User:Jtwsaddress42/People/Neher,_Andrew}} {{User:Jtwsaddress42/People/Negishi, Ei-ichi}} {{User:Jtwsaddress42/People/Noller, Harry F.}} {{User:Jtwsaddress42/Includes/Notes_&_Citations}} {{User:Jtwsaddress42/Navigation/Footer Navbar}} ggxuq9c4q7473kcdzd0vah8aaru9m3p 2 277873 2408215 2337853 2022-07-20T20:12:59Z Jtwsaddress42 234843 /* Arendt, Detlev */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.embl.org/groups/arendt/ Arendt, Detlev] === '''Notable Accomplishments''' * Evolutionary Developmental Biologist <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Arendt,_Detlev}} '''Videos''' <br /> * [https://www.youtube.com/watch?v=Y50nlEmXTjY Detlev Arendt: 10-on-10: The Chronicles of Evolution] * [https://www.youtube.com/watch?v=crL9V86sRec Detlev Arendt: Whole-Body Correlation Of Gene Expression With Single-Cell Morphology] {{RoundBoxBottom}} <hr /> d1wnn48rzrnjgewfzblgp5svycwiz35 2408216 2408215 2022-07-20T20:13:57Z Jtwsaddress42 234843 /* Arendt, Detlev */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.embl.org/groups/arendt/ Arendt, Detlev] === '''Notable Accomplishments''' * Evolutionary Developmental Biologist * Dorsal-Ventral Axis Inversion Theory <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Arendt,_Detlev}} '''Videos''' <br /> * [https://www.youtube.com/watch?v=Y50nlEmXTjY Detlev Arendt: 10-on-10: The Chronicles of Evolution] * [https://www.youtube.com/watch?v=crL9V86sRec Detlev Arendt: Whole-Body Correlation Of Gene Expression With Single-Cell Morphology] {{RoundBoxBottom}} <hr /> 3ljqloygh3n5b39brv7gwr1098gqots 2408217 2408216 2022-07-20T20:19:17Z Jtwsaddress42 234843 /* Arendt, Detlev */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.embl.org/groups/arendt/ Arendt, Detlev] === '''Notable Accomplishments''' * Evolutionary Developmental Biologist * Dorsal-Ventral Axis Inversion Theory <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Arendt,_Detlev}} <hr /> Nübler-Jung et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Nübler-Jung, K.}} <br /><hr/> '''Videos''' <br /> * [https://www.youtube.com/watch?v=Y50nlEmXTjY Detlev Arendt: 10-on-10: The Chronicles of Evolution] * [https://www.youtube.com/watch?v=crL9V86sRec Detlev Arendt: Whole-Body Correlation Of Gene Expression With Single-Cell Morphology] {{RoundBoxBottom}} <hr /> a9tkelg21pkkm42mysddqbfqyqs3q2p 2408325 2408217 2022-07-21T06:19:26Z Jtwsaddress42 234843 /* Arendt, Detlev */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.embl.org/groups/arendt/ Arendt, Detlev] === <hr /> '''Notable Accomplishments''' * Evolutionary Developmental Biologist * Dorsal-Ventral Axis Inversion Theory <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Arendt,_Detlev}} <hr /> Nübler-Jung et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Nübler-Jung, K.}} <br /><hr/> '''Videos''' <br /> * [https://www.youtube.com/watch?v=Y50nlEmXTjY Detlev Arendt: 10-on-10: The Chronicles of Evolution] * [https://www.youtube.com/watch?v=crL9V86sRec Detlev Arendt: Whole-Body Correlation Of Gene Expression With Single-Cell Morphology] {{RoundBoxBottom}} <hr /> bdhj47gjdpcarwil2xecx4rbct4tsdu 2 277874 2408219 2407543 2022-07-20T20:24:11Z Jtwsaddress42 234843 /* Aston, Francis W. (1877 – 1945) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Francis William Aston|Aston, Francis W. (1877 – 1945)]] === [[File:Francis William Aston.jpg|thumb|Francis William Aston (1877 – 1945)]] [[File:Solvay conference, 1922.jpg|thumb|First Solvay conference on Chemistry, 1922 {{efn|First Solvay conference on Chemistry, 1922:<br/>Back Row - Georges Chavanne, Octave Dony-Hénault, Frédéric Swarts, Charles-Victor Mauguin, Édouard Herzen, L. Flamache, Edouard Hannon, Auguste Piccard<br/>Middle Row - Marcel Delépine, Einar Biilmann, Henri Wuyts, Thomas Martin Lowry, Georges Urbain, Jean Perrin, Frans Maurits Jaeger, André Louis Debierne, Hans Rupe, Alfred Berthoud, R.-H. Pickard<br/>Front Row - Charles Moureu, Francis William Aston, Sir William Henry Bragg, Henry Edward Armstrong, Sir William Jackson Pope, Ernest Solvay, Albin Haller, Svante Arrhenius, Frederick Soddy}} - Francis Aston sits front row, second on left side.]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1922/aston/facts/ The Nobel Prize in Chemistry 1922] - "for his discovery, by means of his mass spectrograph, of isotopes, in a large number of non-radioactive elements, and for his enunciation of the whole-number rule." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Aston,_Francis_W.}} <br /><hr /> {| align= center |'''Replica of Francis William Aston's Third Mass Spectrometer''' [[File:Early Mass Spectrometer (replica).jpg|640px|Early Mass Spectrometer (replica)]] <br /> |} {{RoundBoxBottom}} <hr /> ozw6r9m7q1i1voak0edcuj6xd8955ob 2408327 2408219 2022-07-21T06:20:25Z Jtwsaddress42 234843 /* Aston, Francis W. (1877 – 1945) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Francis William Aston|Aston, Francis W. (1877 – 1945)]] === <hr /> [[File:Francis William Aston.jpg|thumb|Francis William Aston (1877 – 1945)]] [[File:Solvay conference, 1922.jpg|thumb|First Solvay conference on Chemistry, 1922 {{efn|First Solvay conference on Chemistry, 1922:<br/>Back Row - Georges Chavanne, Octave Dony-Hénault, Frédéric Swarts, Charles-Victor Mauguin, Édouard Herzen, L. Flamache, Edouard Hannon, Auguste Piccard<br/>Middle Row - Marcel Delépine, Einar Biilmann, Henri Wuyts, Thomas Martin Lowry, Georges Urbain, Jean Perrin, Frans Maurits Jaeger, André Louis Debierne, Hans Rupe, Alfred Berthoud, R.-H. Pickard<br/>Front Row - Charles Moureu, Francis William Aston, Sir William Henry Bragg, Henry Edward Armstrong, Sir William Jackson Pope, Ernest Solvay, Albin Haller, Svante Arrhenius, Frederick Soddy}} - Francis Aston sits front row, second on left side.]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1922/aston/facts/ The Nobel Prize in Chemistry 1922] - "for his discovery, by means of his mass spectrograph, of isotopes, in a large number of non-radioactive elements, and for his enunciation of the whole-number rule." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Aston,_Francis_W.}} <br /><hr /> {| align= center |'''Replica of Francis William Aston's Third Mass Spectrometer''' [[File:Early Mass Spectrometer (replica).jpg|640px|Early Mass Spectrometer (replica)]] <br /> |} {{RoundBoxBottom}} <hr /> hvic2fz0ovstsygs7ijof8d512hovd3 2 277875 2408326 2407542 2022-07-21T06:19:58Z Jtwsaddress42 234843 /* Arrehenius, Svante (1859 – 1927) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Svante Arrhenius|Arrehenius, Svante (1859 – 1927)]] === <hr /> [[File:Svante Arrhenius 01.jpg|thumb|Svante Arrhenius (1859 – 1927)]] [[File:Solvay conference, 1922.jpg|thumb|First Solvay conference on Chemistry, 1922{{efn|First Solvay conference on Chemistry, 1992:<br/>Back Row - Georges Chavanne, Octave Dony-Hénault, Frédéric Swarts, Charles-Victor Mauguin, Édouard Herzen, L. Flamache, Edouard Hannon, Auguste Piccard<br/>Middle Row - Marcel Delépine, Einar Biilmann, Henri Wuyts, Thomas Martin Lowry, Georges Urbain, Jean Perrin, Frans Maurits Jaeger, André Louis Debierne, Hans Rupe, Alfred Berthoud, R.-H. Pickard<br/>Front Row - Charles Moureu, Francis William Aston, Sir William Henry Bragg, Henry Edward Armstrong, Sir William Jackson Pope, Ernest Solvay, Albin Haller, Svante Arrhenius, Frederick Soddy}} - Svante Arrhenius sits first row, second to last, on the right side.]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1903/arrhenius/facts/ The Nobel Prize in Chemistry 1903] - "in recognition of the extraordinary services he has rendered to the advancement of chemistry by his electrolytic theory of dissociation." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Arrehenius,_Svante}} {{RoundBoxBottom}} <hr /> nd0mxod8tpa2yo0wjhqoht7fthu14ym 2 277876 2408334 2407550 2022-07-21T06:25:43Z Jtwsaddress42 234843 /* Bohm, David (1917 – 1992) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:David Bohm|Bohm, David (1917 – 1992)]] === <hr /> [[File:David Bohm.jpg|thumb|David Bohm (1917 – 1992)]] [[File:Doppelspalt.svg|thumb|Simulation of 2 slit experiment in Bohmian mechanics]] [[File:Aharonov-Bohm effect.svg|thumb|Aharonov-Bohm effect{{efn|Schematic of double-slit experiment in which Aharonov–Bohm effect can be observed: electrons pass through two slits, interfering at an observation screen, with the interference pattern shifted when a magnetic field B is turned on in the cylindrical solenoid}}]] '''Notable Accomplishments''' * de Broglie–Bohm theory * Aharonov-Bohm Effect * Wholeness and The Implicate Order * Bohm-Krishnamurti Dialogs <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Bohm,_David}} <hr /> Krishnamurti et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Krishnamurti & Bohm}} '''Related Material''' {{User:Jtwsaddress42/Bibliography/Friedman, Norman}} {{User:Jtwsaddress42/Bibliography/Hiley, Basil J.}} {{User:Jtwsaddress42/Bibliography/Peat 1997}} {{RoundBoxBottom}} <hr /> 2ukce9ygmexphjbmakwmoflf04x5lzo 2 277877 2408212 2407114 2022-07-20T20:08:42Z Jtwsaddress42 234843 /* Bonner, John Tyler (1920 – 2019) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:John_Tyler_Bonner|Bonner, John Tyler (1920 – 2019)]] === '''Notable Accomplishments''' * Professor in the Department of Ecology and Evolutionary Biology at Princeton University * Evolutionary Developmental Biologist <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Bonner,_John_Tyler}} {{RoundBoxBottom}} <hr /> 5midlc4ug1oettmktm67trvj0jgqgnz 2408335 2408212 2022-07-21T06:27:15Z Jtwsaddress42 234843 /* Bonner, John Tyler (1920 – 2019) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:John_Tyler_Bonner|Bonner, John Tyler (1920 – 2019)]] === <hr /> '''Notable Accomplishments''' * Professor in the Department of Ecology and Evolutionary Biology at Princeton University * Evolutionary Developmental Biologist <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Bonner,_John_Tyler}} {{RoundBoxBottom}} <hr /> j6avk6ezbvq1kckuawljy722qbvtkt3 2 277878 2408214 2407119 2022-07-20T20:11:23Z Jtwsaddress42 234843 /* Buss, Leo W. (1953 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Leo_Buss|Buss, Leo W. (1953 - )]]=== '''Notable Accomplishments''' * Professor at Yale University's departments of geology, geophysics, and ecology and evolutionary biology. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Buss,_Leo_W.}} {{RoundBoxBottom}} <hr /> 1tu7a2qvt3dd5i8q60535h7vc4pmfex 2408339 2408214 2022-07-21T06:30:55Z Jtwsaddress42 234843 /* Buss, Leo W. (1953 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Leo_Buss|Buss, Leo W. (1953 - )]]=== <hr /> '''Notable Accomplishments''' * Professor at Yale University's departments of geology, geophysics, and ecology and evolutionary biology. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Buss,_Leo_W.}} {{RoundBoxBottom}} <hr /> auzze71gq5wzlem7c2n9wq2pc52zvvw 2 277879 2408210 2407112 2022-07-20T20:06:47Z Jtwsaddress42 234843 /* Black, Ira B. (1941 – 2006) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ira_Black|Black, Ira B. (1941 – 2006)]] === '''Notable Accomplishments''' * Physician and Neuroscientist * Advocate for Stem Cell Research <br /> <hr /> {{User:Jtwsaddress42/Quotes/Black, Ira B. 1986a}} {{User:Jtwsaddress42/Quotes/Black, Ira B. 1994a}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Black,_Ira_B.}} {{RoundBoxBottom}} <hr /> kubycmwvl2ja1yvrlr2te5oma070z7r 2408331 2408210 2022-07-21T06:23:18Z Jtwsaddress42 234843 /* Black, Ira B. (1941 – 2006) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ira_Black|Black, Ira B. (1941 – 2006)]] === <hr /> '''Notable Accomplishments''' * Physician and Neuroscientist * Advocate for Stem Cell Research <br /> <hr /> {{User:Jtwsaddress42/Quotes/Black, Ira B. 1986a}} {{User:Jtwsaddress42/Quotes/Black, Ira B. 1994a}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Black,_Ira_B.}} {{RoundBoxBottom}} <hr /> 6ilpb6psb54kemi18dr6k5honkr8cqk 2408332 2408331 2022-07-21T06:23:51Z Jtwsaddress42 234843 /* Black, Ira B. (1941 – 2006) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ira_Black|Black, Ira B. (1941 – 2006)]] === <hr /> '''Notable Accomplishments''' * Physician and Neuroscientist * Advocate for Stem Cell Research <br /><hr /> {{User:Jtwsaddress42/Quotes/Black, Ira B. 1986a}} {{User:Jtwsaddress42/Quotes/Black, Ira B. 1994a}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Black,_Ira_B.}} {{RoundBoxBottom}} <hr /> 3mz6rm8pscs5mqyn95t0zu6gwbqtpn1 2 277880 2408206 2407095 2022-07-20T20:04:20Z Jtwsaddress42 234843 /* Berthoz, Alain (1939 - ) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:Alain Berthoz|Berthoz, Alain (1939 - )]] === '''Notable Accomplishments''' * Integrative physiologist focused on multisensory control of gaze, balance, locomotion and spatial memory. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Berthoz,_Alain}} {{RoundBoxBottom}} <hr /> i00b8cvcjpdlg1v26zkiape7tq1nl0d 2408328 2408206 2022-07-21T06:21:04Z Jtwsaddress42 234843 /* Berthoz, Alain (1939 - ) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:Alain Berthoz|Berthoz, Alain (1939 - )]] === <hr /> '''Notable Accomplishments''' * Integrative physiologist focused on multisensory control of gaze, balance, locomotion and spatial memory. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Berthoz,_Alain}} {{RoundBoxBottom}} <hr /> duh374yyticzba7hci3hnj1qfxdn8in 2408329 2408328 2022-07-21T06:21:14Z Jtwsaddress42 234843 /* Berthoz, Alain (1939 - ) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:Alain Berthoz|Berthoz, Alain (1939 - )]] === <hr /> '''Notable Accomplishments''' * Integrative physiologist focused on multisensory control of gaze, balance, locomotion and spatial memory. <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Berthoz,_Alain}} {{RoundBoxBottom}} <hr /> tezqsmkt8je2ai1voxzerf0qstyp25h 2 277881 2408342 2408134 2022-07-21T06:35:30Z Jtwsaddress42 234843 /* Cavalier-Smith, Thomas (1942 - 2021) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Thomas Cavalier-Smith|Cavalier-Smith, Thomas (1942 - 2021)]] === <hr /> '''Notable Accomplishments''' * Classification of Organisms * Obcell Theory * Neomuran Theory <br /> <hr /> {{User:Jtwsaddress42/Includes/Project Box - Remembering Thomas Cavalier-Smith}} {{User:Jtwsaddress42/Gallery/The_Neomuran_Revolution}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith,_Thomas_2010a(a)}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2010a(b)}} {{User:Jtwsaddress42/Gallery/Animal Origins}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017a}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017b}} {{User:Jtwsaddress42/Quotes/Cavalier-Smith, Thomas 2017c}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Cavalier-Smith,_Thomas}} <br /> '''Web Resources''' * [https://royalsociety.org/people/thomas-cavalier-smith-11202/ The Royal Society - Cavalier-Smith, Thomas (1942 - 2021)] {{RoundBoxBottom}} <hr /> hdiiqs4xz99xui8tlgwessy1pzde6kw 2 277882 2408340 2407110 2022-07-21T06:33:21Z Jtwsaddress42 234843 /* Calvin, William H. (1939 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:William_H._Calvin|Calvin, William H. (1939 - )]] === <hr /> [[File:William Calvin-9Aug2008.jpg|thumb|William Calvin (1939 - )]] '''Publications''' {{User:Jtwsaddress42/Bibliography/Calvin,_William_H.}} {{RoundBoxBottom}} <hr /> 3xg9uy23dnbwj4c89vghxobcyt04157 2 277883 2408343 2407574 2022-07-21T06:36:11Z Jtwsaddress42 234843 /* Changeux, Jean-Pierre (1936 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Jean-Pierre_Changeux|Changeux, Jean-Pierre (1936 - )]] === <hr /> [[File:JPChangeux-small.jpg|thumb|Jean-Pierre Changeux (1936 - )]] [[File:Allostery.png|thumb|Allostery]] [[File:NAChR.png|thumb|NAChR]] '''Notable Accomplishments''' * [[w:Monod-Wyman-Changeux model|Monod-Wyman-Changeux (MWC) Model]] of Allosteric Regulation * Isolation of [[w:Nicotinic acetylcholine receptor|Nicotinic Acetylcholine Receptors (NAChRs)]] * Theory of Selective Stabilization at Synapses <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Changeux,_Jean-Pierre}} {{RoundBoxBottom}} <hr /> g84cdmd0d9flcjj08dw2zc8zeyw7hk0 2 277884 2408345 2406901 2022-07-21T06:38:22Z Jtwsaddress42 234843 /* Cisek, Paul */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://cisek.org/pavel/ Cisek, Paul] === <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Cisek,_Paul}} {{RoundBoxBottom}} <hr /> soowucpqqulaptyn1e2kmejjgi9h5g1 2 277886 2408346 2408105 2022-07-21T06:40:30Z Jtwsaddress42 234843 /* Darwin, Charles (1809 - 1882) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Charles_Darwin|Darwin, Charles (1809 - 1882)]] === <hr /> [[File:Charles-darwin-portrait-svg.svg|thumb|Charles Darwin (1809 – 1882)]] '''Notable Accomplishments''' * The Theory of Natural Selection <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Darwin,_Charles}} '''Web Resources''' * [http://darwin-online.org.uk/Freeman_intro.html Darwin Online] * [https://www.darwinproject.ac.uk/ Darwin Correspondence Project] * [https://www.khanacademy.org/science/ap-biology/natural-selection/natural-selection-ap/a/darwin-evolution-natural-selection Khan Academy - Darwin, evolution, & natural selection] <br /><hr /> {{User:Jtwsaddress42/Gallery/The Darwinian Revolution}} {{RoundBoxBottom}} <hr /> b1pa1nlvtov05k0iugmo2pbo4wjxubu 2 277887 2408347 2408110 2022-07-21T06:41:08Z Jtwsaddress42 234843 /* Descartes, René (1596 - 1650) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Rene_Descartes|Descartes, René (1596 - 1650)]] === <hr /> [[File:Portrait of René Descartes, bust, three-quarter facing left in an oval border, (white background removed).png|thumb|René Descartes (1596 - 1650)]] [[File:Descartes Discours de la Methode.jpg|thumb|Descartes Discours de la Methode]] '''Notable Accomplishments''' * Meditations on First Philosophy * Discourse On The Method <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Descartes,_René}} {{RoundBoxBottom}} <hr /> czs3crwuqhn9pjdhisyrntcbf28dlri 2408348 2408347 2022-07-21T06:42:07Z Jtwsaddress42 234843 /* Descartes, René (1596 - 1650) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Rene_Descartes|Descartes, René (1596 - 1650)]] === <hr /> [[File:Portrait of René Descartes, bust, three-quarter facing left in an oval border, (white background removed).png|thumb|René Descartes (1596 - 1650)]] [[File:Descartes Discours de la Methode.jpg|thumb|Descartes Discours de la Methode]] '''Notable Accomplishments''' * Meditations on First Philosophy * Discourse On The Method <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Descartes,_René}} {{RoundBoxBottom}} <hr /> 0tv4vmxq0m5tesrj3tyyajncfg1004v 2 277896 2408353 2407585 2022-07-21T06:44:33Z Jtwsaddress42 234843 /* Edelman, Gerald M. (1929 - 2014) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Gerald_Edelman|Edelman, Gerald M. (1929 - 2014)]] === <hr /> [[File:Professor Gerald M. Edelman.jpg|thumb|Gerald Maurice Edelman (1929 - 2014)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1972/edelman/facts/ The Nobel Prize in Physiology or Medicine 1972] - shared with Rodney Porter "for their discoveries concerning the chemical structure of antibodies." * Neural Darwinism - Theory of Neuronal Group Selection * Topobiology - Molecular Embryology <br /> <hr /> {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1974a}} <br clear=both /><hr /> {{User:Jtwsaddress42/Gallery/The Immune System}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1975a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1978a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1984(a)a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)b}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)c}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)d}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)e}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1987(a)f}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1988(a)a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1988(a)b}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1988(a)c}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1988(a)d}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1989a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1992(a)a}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1992(a)b}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1992(a)c}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1992(a)d}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1992(a)e}} {{User:Jtwsaddress42/Quotes/Edelman, Gerald M. 1998a}} <br clear=both /><hr /> {{User:Jtwsaddress42/Gallery/Degeneracy}} <br clear=both /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Edelman,_Gerald_M.}} <br clear=both /><hr /> {{User:Jtwsaddress42/Bibliography/Edelman et al.}} <br clear=both /><hr /> {{User:Jtwsaddress42/Gallery/NSI Campus}} {{RoundBoxBottom}} <hr /> 8udc4v3pql9mxs7mz3iw0ko1bs5af0v 2 277925 2408287 2320406 2022-07-21T05:11:21Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last= Calvin | first= William H.| year= 1988 | publication-date= June 24, 1988 | title= A Global Brain Theory: Neural Darwinism. The Theory of Neuronal Group Selection | journal= Science | volume= 240 | number= 4860 | pages= 1802 | doi= 10.1126/science.240.4860.1802 | pmid= 17842436 | url= https://science.sciencemag.org/content/240/4860/1802.long }} * {{cite book | last= Calvin, William H. | year= 1991 | title= The Ascent of Mind: Ice Age Climates and The Evolution of Intelligence | publisher= Bantam Books | isbn= 978-0-553-07084-2 | url= https://williamcalvin.com/bk5/bk5.htm }} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} * {{cite book | last1= Calvin | first1= William H. | last2= Ojemann | first2= George A. | year= 1994 | title= Conversations with Neil&acute;s Brain: The Neural Nature Of Thought And Language | publisher= Addison-Wesley | publication-date= September 22, 2010 | isbn= 978-0-982-91676-6 | url= https://www.google.com/books/edition/Conversations_with_Neil_s_Brain/--k_I_UOQKAC?hl=en&gbpv=0 }} 591nxp3gfqxjk6ufrpbqv258houq1kc 2 277934 2408357 2407691 2022-07-21T06:48:11Z Jtwsaddress42 234843 /* Feynman, Richard Phillips (1918 - 1988) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Richard_Feynman|Feynman, Richard Phillips (1918 - 1988)]] === <hr /> [[File:Richard Feynman 1988.png|thumb|Richard Feynman (1918 - 1988)]] [[File:Feynman EP Annihilation.svg|thumb|Feynman EP Annihilation]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/physics/1965/feynman/facts/ The Nobel Prize in Physics 1965] - shared with Sin-Itiro Tomonaga and Julian Schwinger "for their fundamental work in quantum electrodynamics, with deep-ploughing consequences for the physics of elementary particles." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Feynman, Richard Phillips}} '''Cal-Tech Lectures''' <br /> * [https://www.feynmanlectures.caltech.edu/ The Feynman Lectures on Physics Vol. I,II,&III] {{RoundBoxBottom}} <hr /> 3xkqgzasz2gyt27ans4w8tw8tyksnji 2 277937 2408361 2407221 2022-07-21T06:50:30Z Jtwsaddress42 234843 /* Gould, Stephen J. (1941 - 2002) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Stephen_Jay_Gould|Gould, Stephen J. (1941 - 2002)]] === <hr /> [[File:Sjg signature.svg|thumb|Stephen Jay Gould (1941 - 2002)]] [[File:PunctuatedEquilibrium.png|thumb|Punctuated Equilibrium Vs. Phyletic Gradualism]] '''Publications''' {{User:Jtwsaddress42/Bibliography/Gould,_Stephen_J.}} {{RoundBoxBottom}} <hr /> c3tlxzq83bof2dzmf37xj765qbubjzu 2 277939 2408364 2407225 2022-07-21T06:52:36Z Jtwsaddress42 234843 /* Hall, Brian K. (1941 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Brian_K._Hall|Hall, Brian K. (1941 - )]] === <hr /> {{User:Jtwsaddress42/Quotes/Hall, Brian K. 2000a}} '''Publications''' {{User:Jtwsaddress42/Bibliography/Hall,_Brian_K.}} {{RoundBoxBottom}} <hr /> ngg2dkw5b7qjfk4dfuy0a64cuhz1ap6 2408365 2408364 2022-07-21T06:53:15Z Jtwsaddress42 234843 /* Hall, Brian K. (1941 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Brian_K._Hall|Hall, Brian K. (1941 - )]] === <hr /> {{User:Jtwsaddress42/Quotes/Hall, Brian K. 2000a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Hall,_Brian_K.}} {{RoundBoxBottom}} <hr /> rowkhj78avda7zishr5eacpk5mjsr9p 2 277942 2408366 2407227 2022-07-21T06:53:57Z Jtwsaddress42 234843 /* Hamburger, Viktor (1900 - 2001) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Viktor_Hamburger|Hamburger, Viktor (1900 - 2001)]] === <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Hamburger,_Viktor}} {{RoundBoxBottom}} <hr /> gfvv02j2mk11q34dzl6ovda2k6p8wf4 2 277944 2408350 2408111 2022-07-21T06:43:25Z Jtwsaddress42 234843 /* Dubrovsky, Bernardo (1938 - 2016) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.mcgill.ca/psychiatry/channels/news/obituary-dr-bernardo-durbovsky-263526 Dubrovsky, Bernardo (1938 - 2016)] === <hr /> '''Notable Accomplishments''' * Darwinian Evolutionary Psychiatry <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dubrovsky,_Bernardo}} {{RoundBoxBottom}} <hr /> tkmv4npac9fo7d2xdf7l3hunibbc5cp 2408351 2408350 2022-07-21T06:43:36Z Jtwsaddress42 234843 /* Dubrovsky, Bernardo (1938 - 2016) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.mcgill.ca/psychiatry/channels/news/obituary-dr-bernardo-durbovsky-263526 Dubrovsky, Bernardo (1938 - 2016)] === <hr /> '''Notable Accomplishments''' * Darwinian Evolutionary Psychiatry <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dubrovsky,_Bernardo}} {{RoundBoxBottom}} <hr /> 9dpzrkwdtemut5l7p8xwx0nm4fmrew0 2 277947 2408352 2408122 2022-07-21T06:44:08Z Jtwsaddress42 234843 /* Eccles, John C. (1903 - 1997) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:John_Eccles_(neurophysiologist)|Eccles, John C. (1903 - 1997)]] === <hr /> [[File:Sir John Eccles Wellcome L0026812.jpg|thumb|Sir John Eccles (1903 - 1997){{efn|Wellcome_L0026812}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1963/eccles/facts/ The Nobel Prize in Physiology or Medicine 1963] - shared with Alan Hodgkin and Andrew Huxley, "for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Eccles,_John C.}} {{RoundBoxBottom}} <hr /> p18gp0ake31q6wjollx6ylyaxqbhbsj 2 277950 2408355 2407162 2022-07-21T06:47:05Z Jtwsaddress42 234843 /* Faraday, Michael (1791 - 1867) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Michael_Faraday|Faraday, Michael (1791 - 1867)]] === <hr /> [[File:M Faraday Th Phillips oil 1842.jpg|thumb|Michael Faraday (1791 - 1867){{efn|portrait by Thomas Phillips (oil, 1842)}}]] '''Publications''' {{User:Jtwsaddress42/Bibliography/Faraday, Michael}} <br /><hr /> {{User:Jtwsaddress42/Gallery/Michael Faraday}} {{RoundBoxBottom}} <hr /> sq8exvlz6s4yc8kcoieu6qfp6scetxh 2 277951 2408356 2407606 2022-07-21T06:47:37Z Jtwsaddress42 234843 /* Fermi, Enrico (1901 - 1954) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Enrico_Fermi|Fermi, Enrico (1901 - 1954)]] === <hr /> [[File:Enrico Fermi 1943-49.jpg|thumb|Enrico Fermi (1901 - 1954)]] [[File:Beta-minus Decay.svg|thumb|Fermi and Pauli postulated that a neutrino (<math>\bar{\nu}_e</math>) would be emitted during Beta Decay.]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/physics/1938/fermi/facts/ The Nobel Prize in Physics 1938] - "for his demonstrations of the existence of new radioactive elements produced by neutron irradiation, and for his related discovery of nuclear reactions brought about by slow neutrons." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Fermi,_Enrico}} <br /><hr /> {| align= center |'''Stagg Field Reactor''' ''Chicago Pile-1, the first nuclear reactor to achieve a self-sustaining chain reaction''<br /> [[File:Stagg Field reactor.jpg|640px|Stagg Field reactor]] <br/> |} {{RoundBoxBottom}} <hr /> h6o6xxod0snvphxwi4rcjukz0pm1zoh 2 278019 2408387 2408068 2022-07-21T07:16:46Z Jtwsaddress42 234843 /* Onsager, Lars (1903 – 1976) */ wikitext text/x-wiki <br clear= both /> {{RoundBoxTop|theme=3}} === [[w:Lars_Onsager|Onsager, Lars (1903 – 1976)]] === <hr /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1968/onsager/facts/ The Nobel Prize in Chemistry 1968] - “for the discovery of the reciprocal relations bearing his name, which are fundamental for the thermodynamics of irreversible processes.” <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Onsager, Lars}} {{RoundBoxBottom}} <hr /> moa6ylyvyvs6wfwko1inoxvfpep3ckg 2 278020 2408389 2408069 2022-07-21T07:18:09Z Jtwsaddress42 234843 /* Oparin, Aleksandr Ivanovich (1894 – 1980) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Alexander_Oparin|Oparin, Aleksandr Ivanovich (1894 – 1980)]] === <hr /> [[File:Oparin.jpg|thumb|Aleksandr Oparin (1894 – 1980)]] '''Notable Accomplishments''' * First serious chemical theory on the Origin of Life * Coacervates <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Oparin, Aleksandr Ivanovich}} {{RoundBoxBottom}} <hr /> n6h94ucj0s90lzenv7jubodiluoi52c 2 278021 2408390 2407247 2022-07-21T07:18:40Z Jtwsaddress42 234843 /* Orgel, Leslie E. (1927 – 2007) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Leslie_Orgel|Orgel, Leslie E. (1927 – 2007)]] === <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Orgel, Leslie E.}} {{RoundBoxBottom}} <hr /> 6ndi5jndpcwao5f1zw5fiqmc2gcz06h 2 278103 2408360 2407218 2022-07-21T06:50:00Z Jtwsaddress42 234843 /* Gilbert, Scott F. (1949 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Scott_F._Gilbert|Gilbert, Scott F. (1949 - )]] === <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Gilbert, Scott F.}} {{RoundBoxBottom}} <hr /> s3ybv2ila2qcszxwvfs1ecnbp9ju7ca 2 278105 2408359 2407217 2022-07-21T06:49:16Z Jtwsaddress42 234843 /* Gee, Henry (1962 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Henry_Gee|Gee, Henry (1962 - )]] === <hr /> [[File:Henry Gee, December 2008.jpg|thumb|Henry Gee (1962 - )]] '''Publications''' {{User:Jtwsaddress42/Bibliography/Gee, Henry}} {{RoundBoxBottom}} <hr /> hxvyk2sbpny67ebtydmnpzaxqkt1fst 2 278672 2408262 2408067 2022-07-21T03:55:46Z Jtwsaddress42 234843 /* Metchnikoff, Élie (1845 - 1916) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Paul Ehrlich “in recognition of their work on immunity.” <br /><hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} '''Publications'''<br /> {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> jwcxvroyka7yykbybc3ovf7tvm64k7a 2408377 2408262 2022-07-21T07:02:08Z Jtwsaddress42 234843 /* Metchnikoff, Élie (1845 - 1916) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === <hr /> [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Paul Ehrlich “in recognition of their work on immunity.” <br /><hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} '''Publications'''<br /> {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> phfbh7ts5b5o0hyfhefi91kzcozl3zr 2408378 2408377 2022-07-21T07:02:56Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === <hr /> [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Paul Ehrlich “in recognition of their work on immunity.” <br /><hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} '''Publications'' {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> 163h6affzz0dez9ztj3tox8suunq4qs 2408379 2408378 2022-07-21T07:03:33Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Elie_Metchnikoff|Metchnikoff, Élie (1845 - 1916)]] === <hr /> [[File:Professor Élie Metchnikoff.jpg|thumb|Élie Metchnikoff (1845 - 1916)]] also known as: ''Ilya Ilyich Mechnikov''<br /><br /> '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1908/mechnikov/facts/ The Nobel Prize in Physiology or Medicine 1908] - shared with Paul Ehrlich “in recognition of their work on immunity.” <br /><hr /> {{User:Jtwsaddress42/Gallery/Metchnikoff}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Metchnikoff, Élie}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Bibel, Jan D.}} {{User:Jtwsaddress42/Bibliography/Cooper, Edwin L.}} {{User:Jtwsaddress42/Bibliography/Tauber, Alfred I.}} {{RoundBoxBottom}} <hr /> fpquihej2pgfzjr2xhq3bssv8r4qr7n 2 278684 2408349 2408114 2022-07-21T06:42:35Z Jtwsaddress42 234843 /* Dobzhansky, Theodosius (1900 - 1975) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Theodosius_Dobzhansky|Dobzhansky, Theodosius (1900 - 1975)]] === <hr /> '''Notable Accomplishments''' * Major Contributor to the Modern Synthesis in Biology <br /> {{User:Jtwsaddress42/Quotes/Dobzhansky, Theodosius 1973a}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Dobzhansky, Theodosius}} {{RoundBoxBottom}} <hr /> p747ky7f1t1wf30cwagzh56dundxqkw 0 281195 2408238 2405572 2022-07-21T00:06:05Z Saltrabook 1417466 /* International Diabetes and Hypertension Research Group */ wikitext text/x-wiki ==International Diabetes and Hypertension Research Group== The International Diabetes and Hypertension Research Group for fishers, seafarers and other transport workers was created the 12 Jan 2022 in a Zoom conference by specialists in diabetes epidemiology, diabetology, occupational epidemiology, occupational/maritime medicine and public health from Denmark, Greenland, Spain, France, Panamá. Russia and The Filippines. The aim is to provide a foundation for safe and healthy preventive strategies within the UN Global Sustainable Goals, especially '''Goal 3:''' Good health and well-being for all workers ,'''Goal 4:''' Quality education,'''Goal 8:''' Decent Work and Economic Growth and '''Goal 17''': Partnerships to achieve the goals with the primary tasks. Millions of medical examinations are done every year for seafarers, fishers, truck drivers, loco-, bus- and taxi drivers. Most of them use the non-valid urine-sticks and no valid test for T2D, no A1c or FG. By adding biannual screening of hypertension and diabetes mellitus the target groups can be rescued from loss of workability, loss of QUALies and loss of living years. Screening for hypertension and diabetes is cost-effective and sustainable with low extra cost, possibility for no or small extra visit fee and A1C test around 20-50 USD<ref>https://www.talktomira.com/post/what-is-a-diabetes-screening-test-and-how-much-it-costs</ref> as the target group need to attend to the medical clinics for their obligatory often biannual medical examination, anyway. While the extra cost for A1c blood test might be a problem, then the strategy is to validate and replace A1C with Glukometer test<ref>Chen, Huizhen, Qingtao Yao, Yang Dong, Zhimei Tang, Ruiying Li, Baochao Cai, Ruili Wang, and Qiu Chen. “The Accuracy Evaluation of Four Blood Glucose Monitoring Systems According to ISO 15197:2003 and ISO 15197:2013 Criteria.” Primary Care Diabetes 13, no. 3 (June 2019): 252–58. https://doi.org/10.1016/j.pcd.2018.12.010</ref> <ref>Chubb, S. A. Paul, Kylie Van Minnen, Wendy A. Davis, David G. Bruce, and Timothy M. E. Davis. “The Relationship between Self-Monitoring of Blood Glucose Results and Glycated Haemoglobin in Type 2 Diabetes: The Fremantle Diabetes Study.” Diabetes Research and Clinical Practice 94, no. 3 (December 2011): 371–76. https://doi.org/10.1016/j.diabres.2011.07.038</ref> <ref>Kenning, Matthes, Anselm Puchert, Sabine Berg, and Eckhard Salzsieder. “System Accuracy of the Blood Glucose Monitoring System TD4216.” Journal of Diabetes Science and Technology 14, no. 5 (March 7, 2020): 976–77. https://doi.org/10.1177/1932296820910785.</ref> <ref>Makris, K., L. Spanou, A. Rambaouni-Antoneli, K. Koniari, I. Drakopoulos, D. Rizos, and A. Haliassos. “Relationship between Mean Blood Glucose and Glycated Haemoglobin in Type 2 Diabetic Patients.” Diabetic Medicine: A Journal of the British Diabetic Association 25, no. 2 (February 2008): 174–78. https://doi.org/10.1111/j.1464-5491.2007.02379.x.</ref> <ref>Pashintseva, L. P., V. S. Bardina, I. R. Il’iasov, B. P. Mishchenko, and M. B. Antsiferov. “[The clinical laboratory evaluation of accuracy of portable glucometers ‘Satellite Express’ and ‘Satellite Express mini’].” Klinicheskaia Laboratornaia Diagnostika, no. 11 (November 2011): 33–35.</ref> <ref>Sarwat, S., L. L. Ilag, M. A. Carey, D. S. Shrom, and R. J. Heine. “The Relationship between Self-Monitored Blood Glucose Values and Glycated Haemoglobin in Insulin-Treated Patients with Type 2 Diabetes.” Diabetic Medicine: A Journal of the British Diabetic Association 27, no. 5 (May 2010): 589–92. https://doi.org/10.1111/j.1464-5491.2010.02955.x.</ref> ==[[/Members/]]== ==[[/Screening program for diabetes type 2 and hypertension in seafarers’ routine medical examinations/]]== The program combines the biannual, mandatory clinical fit-for-duty health examinations for seafarers in a Public Health perspective with biannual screening for Diabetes Type 2 and Hypertension. An improved prevention is expected by combining with the "Green-ship" health promotion program. The neglected diagnostic problem that the urine dipstick of low validity erroneously has been used for diagnosis of diabetes type 2 in the fit-for-duty medical examinations, is solved. The study adds a protocol with a ready to use Excel Data Entry scheme for the medical clinics to perform an accurate screening for diabetes mellitus type 2 and hypertension. Sustainability is obtained by having seafarers coming biannually for mandatory medical examination, anyway. With the advantages that extra costs for the screening are minimized and the participation in the screening program will be nearly 100%. Implementation of the protocol in a global perspective is expected to have significant health impact not only for seafarers, but also for other transport workers, the companies and the society. The screening program is derived from the initial two projects: [https://en.wikiversity.org/wiki/Maritime_Health_Research_and_Education-NET/DM2 "Early diagnostics of T2DM via routine medical exams"] and [https://en.wikiversity.org/wiki/Maritime_Health_Research_and_Education-NET/Early_diagnostics_of_hypertension_via_routine_medical_exams "Early diagnostics of Hypertension via routine medical exams"] and include: ==[[/Revision of the ILO Guidelines for medical examination for seafarers/]]== ==[[/Revision of the WHO International Medical Guide for Ships/]]== ==[[/Revision of the Ships Medical Chest/]]== ==[[/Diabetes T2 and Hypertension Research and Education plan 2030/|T2D and HTN Research and Education plan 2030]]== ==[[/Seminars/]]== ==References== 155odvf4j0fl3z5abkpmi9cwy4t9ifu 2 281611 2408271 2407242 2022-07-21T04:27:32Z Jtwsaddress42 234843 /* Neher, Andrew (1937 - 2020) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.legacy.com/us/obituaries/santacruzsentinel/name/andrew-neher-obituary?id=7922272 Neher, Andrew (1937 - 2020)] === '''Notable Accomplishments''' * Cabrillo College Tenured Professor of Psychology * Skeptical Analysis & Methodological Critique <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Neher, Andrew}} <br /> '''Related''' {{User:Jtwsaddress42/Bibliography/Alcock, James}} {{User:Jtwsaddress42/Bibliography/Hukill, Traci}} {{RoundBoxBottom}} <hr /> 36b1phjvjrwvloz869cf15f7wqfdwaa 2408272 2408271 2022-07-21T04:31:35Z Jtwsaddress42 234843 /* Neher, Andrew (1937 - 2020) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.legacy.com/us/obituaries/santacruzsentinel/name/andrew-neher-obituary?id=7922272 Neher, Andrew (1937 - 2020)] === '''Notable Accomplishments''' * Tenured Professor of Psychology Cabrillo College, Aptos, California, 1969—2001. * Skeptical Analysis & Methodological Critique <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Neher, Andrew}} <br /> '''Related''' {{User:Jtwsaddress42/Bibliography/Alcock, James}} {{User:Jtwsaddress42/Bibliography/Hukill, Traci}} {{RoundBoxBottom}} <hr /> ttgopak9kxx584mjuzuz6w4jnrqp4yh 2408276 2408272 2022-07-21T04:46:56Z Jtwsaddress42 234843 /* Neher, Andrew (1937 - 2020) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.legacy.com/us/obituaries/santacruzsentinel/name/andrew-neher-obituary?id=7922272 Neher, Andrew (1937 - 2020)] === '''Notable Accomplishments''' * Tenured Professor of Psychology - Cabrillo College, Aptos, California, 1969—2001. * Skeptical Analysis & Methodological Critique <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Neher, Andrew}} <br /> '''Related''' {{User:Jtwsaddress42/Bibliography/Alcock, James}} {{User:Jtwsaddress42/Bibliography/Hukill, Traci}} {{RoundBoxBottom}} <hr /> it7dl7pu83jmrmeewfti4bmn282j4wa 2408382 2408276 2022-07-21T07:06:23Z Jtwsaddress42 234843 /* Neher, Andrew (1937 - 2020) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://www.legacy.com/us/obituaries/santacruzsentinel/name/andrew-neher-obituary?id=7922272 Neher, Andrew (1937 - 2020)] === <hr /> '''Notable Accomplishments''' * Tenured Professor of Psychology - Cabrillo College, Aptos, California, 1969—2001. * Skeptical Analysis & Methodological Critique <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Neher, Andrew}} <br /> '''Related''' {{User:Jtwsaddress42/Bibliography/Alcock, James}} {{User:Jtwsaddress42/Bibliography/Hukill, Traci}} {{RoundBoxBottom}} <hr /> kuqbkmiw3tpmlkk1on5525b1ytfcp61 2 281997 2408312 2395951 2022-07-21T05:55:29Z Jtwsaddress42 234843 wikitext text/x-wiki '''Universals Of Human Nature''' <hr/> <blockquote>"If we do not like what we see when we look into the mirror honestly,<br />&nbsp;&nbsp;&nbsp;&nbsp;we have every opportunity to do something about it."{{sfn|Chomsky|2005b|p=6, Concluding sentance.}}<br /><br />Noam Chomsky (2005)</blockquote> <!-- Sources and References (Copy to Sources and References section of actively displaying pages * {{cite journal | last= Chomsky | first= Noam | year= 2005b | title= Universals of Human Nature | journal= Psychotherapy and Psychosomatics | volume= 74 | number= 5 | pages= 263–268 | publication-date= August 2005 | pmid= 16088263 | doi= 10.1159/000086316 | url= https://www.karger.com/Article/Abstract/86316 }} -- End of Sources and References section --> 1edk2wbxdhp1lzd045txidbs1z5op8n 0 282144 2408225 2403909 2022-07-20T21:08:37Z Atcovi 276019 rewording wikitext text/x-wiki {{Article info | first1 = Ghadeer | last1 = Bustani | orcid1 = 0000-0002-8250-8793 | first2 = Ahmed | last2 = Al-Dulaimi | orcid2 = 0000-0002-3841-3770 | affiliations = Middle Euphrates Hospital, Iraq; M.Sc student, majoring in anesthesia at the University of Tehran; Islamic University, Najaf, Iraq | first3 = Bara | last3 = Al-Hasan | orcid3 = 0000-0001-6932-727X | first4 = Muhammad Ali | last4 = Hameed | first5 = Aaqib Farique | last5 = Azeez | et_al = <!-- if there are >9 authors, hyperlink to the list here --> | correspondence = bustani@iunajaf.edu.iq | journal = WikiJournal of Medicine | license = <!-- default is CC-BY --> | abstract = '''[[w:Coronavirus disease 2019|Coronavirus disease 2019]]''' (COVID-19) is a life-threatening and highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 ([[w:SARS-CoV-2|SARS-CoV-2]]). The disease is regarded as an international public health concern. No specific treatment for COVID-19, including a [[w:vaccine|vaccine]], has been accessible to the public until recently. This study provides a thorough review of the effects of [[w:corticosteroids|corticosteroids]] as they've been effectively used in anti-inflammatory and immunosuppressive therapy, but they have potential negative drawbacks. The purpose of this article is to offer an insight into the management of COVID-19 patients through the use of corticosteroids. This includes most of the journals, books, magazines, and articles that were published from inception on 31 December 2019 to 30 June 2022 in PubMed, Google Scholar, Scopus, Web of Scenic, Cochrane Library, and Embase. This study involves all relevent articles published before 30 June 2022. We used the results obtained in these studies to judge the utilization of corticosteroids and not the causative calibration. The search strategy included a combination of the following keywords and terms: "COVID-19", "Coronavirus", "SARS-CoV-2", "novel CoV", "corticosteroids", "hydrocortisone", "dexamethasone", "methylprednisolone", "prednisone", "budesonide", and "ciclesonide". The credibility of each article was determined by its reputation, relevancy, and the references the article used. The authors of this study individualistically reviewed the article with a specific focus on the usage of corticosteroids for COVID-19 patients. The exclusion criteria reviews articles related to pediatric and neonate patients with COVID-19, the emergency treatment for COVID-19 patients, patients with a history of epilepsy or neurological, neuromuscular, psychiatric, or blood clotting disorders, and other hereditary diseases that were out of the scope of this study. The research was restricted to studies on humans and articles in the English language. | keywords = COVID-19, Coronavirus, SARS-CoV-2, novel CoV, corticosteroids, hydrocortisone, dexamethasone, methylprednisolone, prednisone, budesonide, ciclesonide }} ==Background== In December 2019, SARS-CoV-2 was first detected in Wuhan, Hubei Province, China. Research into the virus' origins has supported the notion that SARS-CoV-2 first originated from a [[w:Wet market|wet market]] in the city, as many of the initial patients of the coronavirus were stall owners, market employees, or regular visitors to the market. Wuhan was the first city in the world to go under lockdown due to the spread of SARS-CoV-2. In February 2020, the World Health Organization (WHO) renamed the "2019 novel coronavirus" to "COVID-19" as the virus was rampantly spreading across the world<ref name=":0">{{Cite web|url=https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it|title=Naming the coronavirus disease (COVID-19) and the virus that causes it|website=www.who.int|language=en|access-date=2022-02-27}}</ref><ref>{{Cite web|url=https://www.forbes.com/sites/victoriaforster/2020/02/11/coronavirus-gets-a-new-name-covid-19-heres-why-renaming-it-is-important/|title=Coronavirus Gets A New Name: COVID-19. Here’s Why That Is Important|last=Forster|first=Victoria|website=Forbes|language=en|access-date=2022-02-27}}</ref>. On March 11, 2020, the [[w:World Health Organization|World Health Organization]] (WHO) officially designated COVID-19 as the fifth pandemic in written history<ref>{{Cite web|url=https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020|title=WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020|website=www.who.int|language=en|access-date=2022-02-27}}</ref>. COVID-19 is a highly infectious disease that has a reported mortality rate of approximately 3% (May 2020). This percentage is lower than the reported mortality rate of SARS-CoV (10%) and MERS-CoV (35%)<ref>{{Cite journal|last=Pascarella|first=Giuseppe|last2=Strumia|first2=Alessandro|last3=Piliego|first3=Chiara|last4=Bruno|first4=Federica|last5=Del Buono|first5=Romualdo|last6=Costa|first6=Fabio|last7=Scarlata|first7=Simone|last8=Agrò|first8=Felice Eugenio|date=2020-05-13|title=COVID‐19 diagnosis and management: a comprehensive review|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267177/|journal=Journal of Internal Medicine|pages=10.1111/joim.13091|doi=10.1111/joim.13091|issn=0954-6820|pmc=7267177|pmid=32348588}}</ref>. Although a lower mortality rate, the COVID-19 pandemic had a larger worldwide impact. SARS-CoV-2 infects the respiratory system and causes additional damage to the alveolis in the lung<ref>{{Cite journal|last=Dimbath|first=Elizabeth|last2=Maddipati|first2=Veeranna|last3=Stahl|first3=Jennifer|last4=Sewell|first4=Kerry|last5=Domire|first5=Zachary|last6=George|first6=Stephanie|last7=Vahdati|first7=Ali|date=2021-06-01|title=Implications of microscale lung damage for COVID-19 pulmonary ventilation dynamics: A narrative review|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946865/|journal=Life Sciences|volume=274|pages=119341|doi=10.1016/j.lfs.2021.119341|issn=0024-3205|pmc=7946865|pmid=33716059}}</ref>. This causes [[w:Hypoxia|hypoxia]], resulting in organ failure<ref>{{Cite journal|last=Rahman|first=Ahsab|last2=Tabassum|first2=Tahani|last3=Araf|first3=Yusha|last4=Al Nahid|first4=Abdullah|last5=Ullah|first5=Md. Asad|last6=Hosen|first6=Mohammad Jakir|date=2021|title=Silent hypoxia in COVID-19: pathomechanism and possible management strategy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062941/|journal=Molecular Biology Reports|volume=48|issue=4|pages=3863–3869|doi=10.1007/s11033-021-06358-1|issn=0301-4851|pmc=8062941|pmid=33891272}}</ref>. Other possible repercussions include heart inflammation (e.g., [[w:Myocarditis|myocarditis]]), [[w:Liver damage|liver damage]], blood clots (could lead to [[w:Pulmonary embolism|pulmonary embolism]]), and neurological malfunction ([[w:Confusion|confusion]], [[w:Amnesia|amnesia]], [[w:Ageusia|ageusia]], etc.)<ref>{{Cite web|url=https://www.health.harvard.edu/blog/covid-19-and-the-heart-what-have-we-learned-2021010621603|title=COVID-19 and the heart: What have we learned?|date=2021-01-08|website=Harvard Health|language=en|access-date=2022-02-27}}</ref><ref>{{Cite journal|last=Zhong|first=Peijie|last2=Xu|first2=Jing|last3=Yang|first3=Dong|last4=Shen|first4=Yue|last5=Wang|first5=Lu|last6=Feng|first6=Yun|last7=Du|first7=Chunling|last8=Song|first8=Yuanlin|last9=Wu|first9=Chaomin|date=2020-11-02|title=COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms|url=https://www.nature.com/articles/s41392-020-00373-7|journal=Signal Transduction and Targeted Therapy|language=en|volume=5|issue=1|pages=1–8|doi=10.1038/s41392-020-00373-7|issn=2059-3635}}</ref><ref>{{Cite web|url=https://www.hri.org.au/health/your-health/lifestyle/people-with-coronavirus-are-at-risk-of-blood-clots-and-strokes|title=People with coronavirus are at risk of blood clots and strokes • Heart Research Institute|website=Heart Research Institute|language=en-AU|access-date=2022-02-27}}</ref><ref>{{Cite journal|last=Niazkar|first=Hamid Reza|last2=Zibaee|first2=Behdad|last3=Nasimi|first3=Ali|last4=Bahri|first4=Narjes|date=2020-07-01|title=The neurological manifestations of COVID-19: a review article|url=https://doi.org/10.1007/s10072-020-04486-3|journal=Neurological Sciences|language=en|volume=41|issue=7|pages=1667–1671|doi=10.1007/s10072-020-04486-3|issn=1590-3478|pmc=PMC7262683|pmid=32483687}}</ref>. These negative effects can be exacerbated by a [[w:Cytokine storm|cytokine storm]], a dangerous overreaction in the body where the immune system releases an excessive amount of cytokines despite the threat no longer being present. For these various health consequences, around 10–20% of hospitalized patients are admitted to the intensive care unit (ICU), 3–10% require intubation and 2–5% succumb to the disease<ref>{{Cite journal|last=Pascarella|first=Giuseppe|last2=Strumia|first2=Alessandro|last3=Piliego|first3=Chiara|last4=Bruno|first4=Federica|last5=Del Buono|first5=Romualdo|last6=Costa|first6=Fabio|last7=Scarlata|first7=Simone|last8=Agrò|first8=Felice Eugenio|date=2020-05-13|title=COVID‐19 diagnosis and management: a comprehensive review|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267177/|journal=Journal of Internal Medicine|pages=10.1111/joim.13091|doi=10.1111/joim.13091|issn=0954-6820|pmc=7267177|pmid=32348588}}</ref>. Various studies have attempted to find a way to decrease the mortality rate and the severity of COVID-19 symptoms through the use of corticosteroids drugs, as corticosteroids are a useful mechanism in treating [[w:inflammation|inflammation]] and defects in the [[immune system]]<ref>{{Cite journal|last=Williams|first=Dennis M.|date=2018-06-01|title=Clinical Pharmacology of Corticosteroids|url=http://rc.rcjournal.com/content/63/6/655|journal=Respiratory Care|language=en|volume=63|issue=6|pages=655–670|doi=10.4187/respcare.06314|issn=0020-1324|pmid=29794202}}</ref>. === Coronavirus === {{fig|1|SARS-CoV-2 without background.png|size=100px|align=left|A scientifically accurate model of SARS-CoV-2. {{attrib|Alissa Eckert, MS; Dan Higgins, MAM| [[W:Public domain|Public domain]]}}}} '''[[w:Coronavirus|Coronaviruses]]''' (derived from the Latin word ''[[wiktionary:Corona#Latin|corona]]'') are a group of zoonotic RNA viruses in the family ''Coronaviridae'' of the order ''Nidovirales'' that were first isolated in 1937. In 1965, the group of viruses was coined the name "Coronavirus" due to its crown-like appearance observed under a microscope. The species of coronaviruses that have been recorded as of March 2021 are the alpha coronaviruses [[w:Human coronavirus 229E|HCoV-229E]] and [[w:Human coronavirus NL63|HCoV-NL63]]; the beta coronaviruses [[w:Human coronavirus OC43|HCoV-OC43]] and [[w:Human coronavirus HKU1|HCoV-HKU1]]; [[w:Severe acute respiratory syndrome coronavirus 1|SARS-CoV-1]]; [[w:MERS-CoV|MERS-CoV]]; and SARS-CoV-2 (Figure 1 to the left represents a model of this virus)<ref>{{Cite journal|last=Lima|first=Claudio Márcio Amaral de Oliveira|date=2020-04-17|title=Information about the new coronavirus disease (COVID-19)|url=http://www.scielo.br/j/rb/a/MsJJz6qXfjjpkXg6qVj4Hfj/|journal=Radiologia Brasileira|language=en|volume=53|pages=V–VI|doi=10.1590/0100-3984.2020.53.2e1|issn=1678-7099}}</ref>. Coronaviruses can cause severe respiratory complications in humans. In 2002, a strain of coronavirus, known as severe acute respiratory syndrome (SARS), spread to various parts of Asia in 2002. In 2012, another strain of coronavirus, MERS-CoV, affected the Arabian Peninsula in the Middle East<ref>{{Cite journal|last=Azhar|first=Esam I.|last2=Hui|first2=David S. C.|last3=Memish|first3=Ziad A.|last4=Drosten|first4=Christian|last5=Zumla|first5=Alimuddin|date=2019-12-01|title=The Middle East Respiratory Syndrome (MERS)|url=https://www.id.theclinics.com/article/S0891-5520(19)30060-1/abstract|journal=Infectious Disease Clinics|language=English|volume=33|issue=4|pages=891–905|doi=10.1016/j.idc.2019.08.001|issn=0891-5520|pmid=31668197}}</ref>. === Corticosteroids === {{fig|2|Cortisol-3D-balls.png|align=right|A 3D ball-and-stick model of a [[w:cortisol|cortisol]] (C₂₁H₃₀O₅), a steroid hormone. It is known as "hydrocortisone" when used as a medication. {{attrib|[[w:User:Benjah-bmm27|Benjah-bmm27]]| [[W:Public domain|Public domain]]}}}} '''[[w:Corticosteroids|Corticosteroids]]''' are a type of steroid hormones that are used as treatments for a wide variety of health problems. They are secreted from the adrenal glands of vertebrates and are also artifically made. Corticosteroids are divided into two types: the [[w:Glucocorticoids|glucocorticoids]] and [[w:Mineralocorticoids|mineralocorticoids]]. Both of these classes of corticosteroids deal with anti-inflammation and immunosuppressive therapy, but both have specialized roles. The glucocorticoids dial down stress, control metabolism, and control behavior. An example of a glucocotricoid is cortisol (shown in Figure 2). The mineralocorticoids regulate the transportation of sodium and water throughout the body<ref name=":1">{{Cite web|url=https://info.umkc.edu/pharmtofarm/clinical-question-how-are-glucocorticoids-and-mineralocorticoids-different/|title=Clinical Question: How are glucocorticoids and mineralocorticoids different? – Pharm to Farm|website=info.umkc.edu|access-date=2022-02-27}}</ref>. An example of a mineralocorticoid is [[w:Aldosterone|aldosterone]]<ref>{{Cite journal|last=Taves|first=Matthew D.|last2=Gomez-Sanchez|first2=Celso E.|last3=Soma|first3=Kiran K.|date=2011-7|title=Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3275156/|journal=American Journal of Physiology - Endocrinology and Metabolism|volume=301|issue=1|pages=E11–E24|doi=10.1152/ajpendo.00100.2011|issn=0193-1849|pmc=3275156|pmid=21540450}}</ref>. Corticosteroids can be taken in a variety of ways, including IV (injection), tablets, inhalers, rectally, and creams<ref name=":2" /><ref name=":3" />. Which method administered depends on the health condition. ==== Benefits of Corticosteroids ==== Corticosteroids are indicted for their quick ability to reduce inflammation, control overwhelming immune responses, and maintain homeostasis. They are one of the most prescribed drugs in the world<ref name=":2">{{Cite book|url=http://www.ncbi.nlm.nih.gov/books/NBK554612/|title=Corticosteroids|last=Hodgens|first=Alexander|last2=Sharman|first2=Tariq|date=2022|publisher=StatPearls Publishing|location=Treasure Island (FL)|pmid=32119499}}</ref>. Corticosteroids are used to treat inflammation, [[w:Asthma|asthma]], allergies, hives, [[w:Hypoglycemia|hypoglycemia]], neurological disorders, skin disorders, and various other conditions <ref name=":2" /><ref name=":3">{{Cite web|url=https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/corticosteroids|title=Corticosteroids|website=www.nhsinform.scot|language=en|access-date=2022-02-27}}</ref><ref name=":4">{{Cite web|url=https://www.medicalnewstoday.com/articles/corticosteroids|title=Corticosteroids: Types, side effects, and how they work|date=2020-03-18|website=www.medicalnewstoday.com|language=en|access-date=2022-02-27}}</ref>. Corticosteroids can be used in the event of an organ transplant<ref name=":2" />. Corticosteroids can be used to replace hormones that are not being produced sufficiently, such as in the case of adrenal insufficiency in [[w:Addison's disease|Addison's disease]]<ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" />. ==== Side Effects of Corticosteroids ==== === Corticosteroids' Effect on COVID-19 Patients === In cohort studies and case series that used corticosteroids to treat COVID-19 patients, they've yielded conflicting results. Some studies found beneficial effects of corticosteroids while others have found negative effects [5]. In a previous study consisting of a series of six consecutive hospitalized COVID-19 patients with rapidly deteriorating hypoxemia and laboratory indices of COVID-19 associated hyper-inflammatory syndrome (CAHS), all COVID-19 patients made a full recovery following a short course of high-dose corticosteroid (CS) [6]. A previous study suggested that cytokine release syndrome (CRS) could be involved in the pathophysiology of severe or critical COVID-19 cases, frequently resulting in death. Therefore it is essential that the cytokine storm be recognized and suppressed in its early stages in order to save the patient's life [9]. Despite these findings, there isn't sufficient documentation from randomized clinical trials to approve the use of corticosteroids on COVID-19 patients. Although intravenous corticosteroids have been commonly used for patients with severe SARS/MERS pneumonia, their overall efficiency and effectiveness in treating COVID-19 remains argumentative [10]. In an observational study conducted in Wuhu, China from the 24th of January 2020 to the 24th February 2020, the use of corticosteroids in COVID-19 cases were found to have indicated no statistically significant differences in the virologic or clinical outcome between patients who received corticosteroids and those who did not receive corticosteroids [11]. In addition, the use of corticosteroids was not recommended in the treatment of COVID-19 by WHO until 24 June 2020. As a result, many questions regarding the use of corticosteroids in the treatment of COVID-19 patients remain unanswered [12]. However, a study done on June 4, 2020, indicated that severely infected patients of COVID-19 were more likely to require corticosteroids therapy [10]. On June 25, 2020, the National Institutes of Health (NIH) COVID-19 treatment guidelines, based on a preliminary analysis of the data from the Randomised Evaluation of COVID-19 Therapy (RECOVERY), authorized the use of dexamethasone, a corticosteroid, to patients that developed a systemic inflammatory response (potentially leading to lung injury and multi-system organ dysfunction) as a result of COVID-19. For 10 days, the patients were prescribed doses of 6 mg/day. The use of dexamethasone yielded positive consequences in patients with severe COVID-19 (defined as patients who required oxygen therapy) and was observed to have the greatest effect in patients who required mechanical ventilation at the time of enrollment. Simultaneously, no positive effects of dexamethasone were observed in patients who did not require oxygen therapy [5]. In March-July of 2020, a study conducted by Massachusetts General Hospital (MGH) COVID-19 for Treatment Guidance conclusively recommended the use of dexamethasone, both PO (orally) and IV (intravenous) formulations, for patients with mild or moderate COVID-19 infections that eventually progress to oxygen requirement (severe disease). This is because dexamethasone exhibits no mineralocorticoid effects as compared to other steroids. While MGH mentioned that ceasing to inhale steroids may cause or worsen any underlying lung disease, no data has indicated that inhaling corticosteroids worsens COVID-19-related morbidity or mortality [13]. Additionally, a study in India in September-October of 2020 indicated that the use of dexamethasone causes an impressive 35% mortality rate decrease among patients on invasive mechanical ventilation and a 20% mortality rate decrease amongst patients on oxygen therapy (noninvasive ventilation not relevant), but no significant benefit was observed in mild COVID-19 cases [14]. Other steroids that can be used as an alternative for dexamethasone are hydrocortisone (intravenous 50mg every 8hrs), methylprednisolone (intravenous 30mg every day), and prednisone (PO 40mg every day). Unlike the alternatives, dexamethasone exhibits no mineralocorticoid effect. These alternatives would be preferable over dexamethasone in the event of contraindications, such as pregnancy. Dexamethasone is known to have caused negative fetal effects, hypersensitivity, and uncontrolled fungal infection [13]. A document published on July 2, 2020, showed that a daily intake of 20mg IV dexamethasone on days 1-6, followed by a daily intake of 10mg IV dexamethasone, resulted in a decreased duration of mechanical ventilation and overall mortality in comparison to conventional treatment alone [15]. In another study, 2,104 patients were randomly allocated to receive dexamethasone for 28 days. The results of this study are summarized in the table below (table 1) [16]. {| class="wikitable" |+Table 1: Recovery Trial (dexamethasone) for 28 days | |'''Mortality rate with dexamethasone''' |'''Mortality rate with usual care''' |- |'''Patients undergoing oxygen therapy''' |21.5% |25% |- |'''Patients not undergoing oxygen therapy''' |17% |13.2% |- |'''Patients on mechanical ventilator''' |29% |40.7% |} A study published in April 17, 2020 that made comparisons between the treatment guidelines for COVID-19 in Saudi Arabia, the USA, Europe and Egypt referred to the use of '''hydrocortisone''' just in Egypt for critical cases [17]. '''Prednisone''' (or '''methylprednisolone'''), at a dose of 1 mg/kg equivalent per day, was added to a treatment protocol in a hospital in Reims, France. Significant reductions were observed in hospital mortality in patients with COVID-19 pneumonia who developed ARDS , methylprednisolone appeared to reduce the risk of death. 46% of patients died with the use of methylprednisolone, while those who did not receive methylprednisolone (61.8%) died [15]. Additionally, using single-dose pulse methylprednisolone (40- 500mg methylprednisolone) had no apparent negative impact on virus removal and production of specific IgG while effectively stopping the inflammatory cascade [9]. For septic shock, the effect of corticosteroids in COVID-19 patients may be different than the effects seen in those with acute respiratory distress syndrome (ARDS).  The Surviving Sepsis Campaign and NIH suggest the use of low-dose corticosteroid therapy (e.g., hydrocortisone 200 mg daily as an IV infusion or intermittent doses) over no corticosteroid therapy in adults with COVID-19 and refractory shock [15]. The NIH stated that patients who were taking oral corticosteroids therapy for chronic conditions for an underlying condition prior to COVID-19 infection (e.g., primary or secondary adrenal insufficiency, rheumatologic diseases) should not be discontinued. Inhaled corticosteroids used daily for the management of asthma and chronic obstructive pulmonary disease (COPD) to control airway inflammation should not be discontinued in patients with COVID-19 [15]. In this review, we created a table to summarize using glucocorticoid in the  guideline of covid 19 for some countries as indication , dose , rote of administration and the study that dependent in for use (table 2) In this review, we've created a table to summarize the use of glucocorticoid according to the COVID-19 treatment guidelines in various countries (table 2). {| class="wikitable" |+(Table 2) Use of Glucocotricoid in Various Countries according to their COVID-19 Treatment Guidelines | colspan="6" | |- |'''Guidelines and''' '''therapeutic protocols''' |'''Glucocorticoids (GC)''' |'''Route of''' '''Administration''' |'''Indications''' |'''Dose''' |'''Result''' |- |China [18] |methylprednisolon |intravenous, intraosseous |To patients - - severe and critically ill stage; -with resistance high fever (body temperature >39 °C); - computerized tomography (CT) demonstrated patchy ground-glass attenuation or having >30% area of the lungs involved; -whose CT demonstrated rapid progression (>50% area involved in pulmonary CT images within 48 h); -whose IL-6 is above ≥ 5 ULN. <nowiki>*</nowiki>Appropriate and short-term use of GCs should be considered for patients with severe COVID-19 pneumonia as early as possible. <nowiki>*</nowiki>High dosages of methylprednisolon should be avoided due to the possible adverse complications |*Initial methylprednisolon at a dose of 0.75∼1.5 mg/kg IV once a day (nearly 40 mg once or twice a day) is recommended. <nowiki>*</nowiki>MP at a dose of 40 mg q12 h can be considered for patients with falling body temperature or significantly increased cytokines under routine doses of GCs. <nowiki>*</nowiki>MP at a dose of 40 mg–80 mg q12 h can be used for critical cases. <nowiki>*</nowiki>The dosage of MP should be halved every 3–5 days if: -medical conditions of patients improve; -the body temperature normalizes; -involved lesions on CT are significantly absorbed. <nowiki>*</nowiki>Oral MP once a day is recommended when the IV dose is reduced to 20 mg per day. <nowiki>*</nowiki>The length of GC treatment in not defined; some experts have suggested ceasing GC treatment when patients are near to a full recovery. |Observational/Retrospective |- |National Institutes of Health COVID-19 Treatment Guidelines [5] |dexamethasone |orally intravenously |*patients with COVID-19 who are mechanically ventilated <nowiki>*</nowiki>patients with COVID-19 who require supplemental oxygen, but are not mechanically ventilated <nowiki>*</nowiki>not recommend for patients that do not need oxygen therapy |dexamethasone (at a dose of 6 mg per day for up to 10 days) |At this time, it is not known if other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have similar benefits as dexamethasone has. The dose equivalencies for dexamethasone 6mg/day are prednisone 40mg/day, methylprednisolone 32 mg/day, and hydrocortisone 160 mg/day. |- |Italian protocols employed by single institutions [18] |methylprednisolon prednisone |intravenous, intraosseous |Patients admitted to intensive care units that are suspected to have developed ARDS. |* methylprednisolon dose 1 mg/kg/day for 5 days; <nowiki>*</nowiki>Afterwards, reduction to 0.5 mg/kg/day for a further 5 days. <nowiki>*</nowiki>In some protocols. prednisone is used as a latest step (for dose reduction) and is administered per OS. | |- |Study promoted by ASUGI (Azienda Sanitaria Universitaria Giuliano Isontina) in Italy [18] |methylprednisolon |intravenous, intraosseous |patients hospitalized in Pneumology/UTIR (Respiratory Intensive Care Unit) |*Day 1: methylprednisolon: 80 mg IV as bolus, followed by  80 mg in IV continuous infusion in 240 mL of physiological saline solution (0.9%) in 24 h. <nowiki>*</nowiki>The following 8 days: give methylprednisolon, 80 mg in IV continuous infusion in 240 mL of physiological saline solution. (0.9%) in 24 h until reach PaO2/FIO2>350 mmHg and/or C-reactive protein 2≤mg/dL. <nowiki>*</nowiki>When PaO2/FIO2>350 mmHg and/or C-reactive protein ≤2 mg/dl (or ≤20 mg/L): oral intake of methylprednisolon 16 mg twice a day (or IV methylprednisolon<nowiki>:</nowiki> 20 mg twice a day) to reduce until withdrawal when C-reactive protein is normal (±20%) and/or PaO2/FIO2>400 or SatHbO2≥95% in air. |Multicentric non-randomized controlled cohort trial, in patients with COVID-19 linked ARDS. |- |Massachusetts General Hospital (MGH) COVID-19 for Treatment Guidance [13] |Dexamethasone Hydrocortisone Methylprednisolone Prednisone |Intravenous oral intravenous intravenous PO |*Patients with moderate to severe COVID19. *Patients requiring oxygen supply. |Dexamethasone at a dose of 6 mg PO/IV for up to 10 days. Hydrocortisone 50mg q8hrs Methylprednisolone 30mg daily Prednisone 40mg qd | |- |US (Yale University) [18] |Methylprednisolone |intravenous |May be considered for use by critical care team for salvage therapy. <nowiki>*</nowiki>GC should be used if clinically indicated as part of the standard of care, such as for an asthma, COPD exacerbation or shock with history of chronic steroid use. <nowiki>*</nowiki>Lack of effectiveness and potential harm shown in literature, specifically inhibition of viral clearance in severe influenza and SARS, though possible benefit with critically ill COVID19 patients. |Methylprednisolone 40 mg q8hr intravenous for three days, then reassess after three days | |- |United Kingdom [18] |Low-dose dexamethasone |intravenous, intraosseous |Hospitalized patients diagnosed with COVID-19 infection | |Randomized controlled trial (RECOVERY) EudraCT number: 2020−001113- 21 |- |WHO [18] | colspan="5" |Do not routinely give systemic glucocorticoids for treatment of viral pneumonia outside of clinical trials. A systematic review of observational studies of glucocorticoid administered to patients with SARS reported no survival benefit and possible negative consequences (avascular necrosis, psychosis, diabetes, and delayed viral clearance). WHO has prioritized the evaluation of GCs in clinical trials to assess safety and efficacy. |- |US IDSA (Infectious Diseases Society of America) [19] | colspan="5" |For patients admitted to the hospital with COVID-19 pneumonia, the panel suggests against the use of glucocorticoids. The panel recommends the use of GCs in the context of a clinical trial for patients admitted to the hospital with ARDS due to COVID-19. |} Either about inhaled corticosteroids that mentioned in systematic review and clinical perspective that published at April 2020 show in vitro study that inhaled corticosteroid (ciclesonide)have antiviral effect  and also have lower immunosuppressive effects . Furthermore, early, not yet peer-reviewed data, suggest ciclesonide blocks SARS-CoV-2 RNA replication in vitro  and inhibits SARS-CoV-2 cytopathic activity , which may be of great relevance to reducing the risk of developing of COVID-19 in response to SARS-CoV-2 infection or reducing the severity of the disease[20]. And Pre-treatment of human respiratory epithelial cells in vitro with budesonide, in combination with glycopyrronium and formoterol, has inhibitory actions on coronavirus HCoV-229E replication and cytokine production [20] also the asthmatic patients take inhaled steroid all the time is 22-63% from all asthmatic patients [21]. as in Wuhan china 5% of people are have asthma and just 1% of asthmatic patients hospitalized with covid 19 also in new york the asthma is not on the 10 top of core morbidities even as 10% of new york people asthmatic[22].in other hand in one observational study has shown an increased risk of pneumonia or lower respiratory infection [23].In vitro studies have suggested that corticosteroids may impair antiviral innate immune responses and that inhaled corticosteroids use leads to delayed virus clearance[20] . Many studies mention to some adverse effects of using corticosteroids including hyperglycemia, hypernatremia, and hypokalemia  also the WHO does not currently recommend corticosteroids in other viral diseases, like Dengue as the ‘glucocorticoid-mediated stimulation of the hypothalamic- pituitary adrenal axis can also drive lymphocytopenia, or it may promote exaggerated pro-inflammatory responses that eventually cause a worsening of the pathogenic condition[24] Also corticosteroid using may associated with no survival benefit and possible harm (e.g., delayed viral clearance, avascular necrosis, psychosis, diabetes)[15]. ==Conclusion== Regard using dexamethasone In patients hospitalized with COVID-19, this reduced  mortality and duration of mechanical ventilation among those under mechanical ventilation or oxygen support , but not with patients that need oxygen and regard using methylprednisolone as single-dose (40- 500 mg) that had no apparent negative impact on coronavirus removal and production of specific IgG while effectively stopping the inflammatory cascade. For other glucocorticoids (hydrocortisone,Prednisone) have also been shown to reduce the duration of mechanical ventilation and using as alternative to using dexamethasone or methylprednisolone in equivalent dose decrease overall mortality in patients with established moderate-to-severe patient with ARDS and pneumonia with covid 19 who are under mechanically ventilated and  patients Whose are not under mechanically ventilated but need oxygen supply. And about inhaled corticosteroids at this time , there is no evidence as to whether premorbid use or continued administration of it is a factor for adverse or beneficial outcomes in coronavirus ; therefore, corticosteroids should be used with caution in the treatment of COVID-19 . ==Recommendation== Up to last studies we recommending for using dexamethasone or methylprednisolone for patients how need oxygen supply or whose need mechanical ventilation and not for patients that no need oxygen for now. As using it delay the clearance of virus but can using for effective suppression of the cytokine storm for life-saving in severe and critical covid 19 patients. Due to given the paucity of direct evidence and the limitations of indirect evidence we need further multicenter clinical trials  to better understand the role of corticosteroids in COVID-19 to verify from benefits and harmful effects . so when using corticosteroids now  should be careful from harmful effect. At last I hope all people learn lessons especially in terms of public and global health for any future similar pandemics. === Limitations === *''Covid 19 is new and the updates is continuous with each month so it’s difficult to get information that is reliable'' *''The limiting  in data source for covid 19 as its new disease in the word .'' *''Many articles are need for credit card and not as free text'' *''Deficit to get accurate information as it continuous change in each day and I need for newer data'' === Funding === Non, self-funded by authors == References == <references /> == References == {{reflist|35em}}[1]      U. Pradesh ''et al.'', “Coronavirus Disease 2019 – COVID-19 Kuldeep Dhama,” no. April, pp. 1–75, 2020, doi: 10.20944/preprints202003.0001.v2. [2]      T. Global and O. Alert, “Coronavirus disease 2019 ( COVID-19 ),” vol. 2019, no. April, 2020. [3]      G. Pascarella ''et al.'', “COVID-19 diagnosis and management: a comprehensive review,” ''J. Intern. Med.'', no. March, pp. 1–15, 2020, doi: 10.1111/joim.13091. [5]      T. Guidelines, “Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Disponible en: <nowiki>https://covid19treatmentguidelines.nih.gov/.,”</nowiki> vol. 2019, 2019. [6]      L. Kolilekas ''et al.'', “Can steroids reverse the severe COVID‐19 induced ‘cytokine storm’?,” ''J. Med. Virol.'', no. May, pp. 1–4, 2020, doi: 10.1002/jmv.26165. [7]      C. M. A. De Oliveira Lima, “Information about the new coronavirus disease (COVID-19),” ''Radiol. Bras.'', vol. 53, no. 2, pp. v–vi, 2020, doi: 10.1590/0100-3984.2020.53.2e1. [8]      C. Huang ''et al.'', “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China,” ''Lancet'', vol. 395, no. 10223, pp. 497–506, 2020, doi: 10.1016/S0140-6736(20)30183-5. [9]      J. Liu, X. Zheng, Y. Huang, H. Shan, and J. Huang, “Successful use of methylprednisolone for treating severe COVID-19,” ''J. Allergy Clin. Immunol.'', pp. 74–76, 2020, doi: 10.1016/j.jaci.2020.05.021. [10]    D. Editor, G. Ao, and X. Qi, “American Journal of Emergency Medicine,” pp. 40–42, 2020, doi: 10.1016/j.ajem.2020.06.040. [11]    L. Zha ''et al.'', “Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19),” ''Med. J. Aust.'', vol. 212, no. 9, pp. 416–420, 2020, doi: 10.5694/mja2.50577. [12]    A. K. Singh, S. Majumdar, R. Singh, and A. Misra, “Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective,” ''Diabetes Metab. Syndr. Clin. Res. Rev.'', vol. 14, no. 5, pp. 971–978, 2020, doi: 10.1016/j.dsx.2020.06.054. [13]    T. General ''et al.'', “Massachusetts General Hospital ( MGH ) COVID-19 Treatment Guidance P a g e 1 | 21 Table 1 : Work-up for diagnosis , prognosis / risk stratification , and / or safety of therapeutics Suggested for hospitalized patients with confirmed COVID-19 1 Radiology :,” 2020. [14]    A. Kumar, S. Majumdar, R. Singh, and A. Misra, “Diabetes & Metabolic Syndrome : Clinical Research & Reviews Role of corticosteroid in the management of COVID-19 : A systemic review and a Clinician ’ s perspective,” ''Diabetes Metab. Syndr. Clin. Res. Rev.'', vol. 14, no. 5, pp. 971–978, 2020, doi: 10.1016/j.dsx.2020.06.054. [15]    A. Agents and S. Agents, ''Assessment of Evidence for COVID-19-Related Treatments : Updated 4 / 10 / 2020 TABLE OF CONTENTS''. . [16]    H. Ledford, “Coronavirus breakthrough: dexamethasone is first drug shown to save lives,” ''Nature'', vol. 582, no. 7813, p. 469, Jun. 2020, doi: 10.1038/d41586-020-01824-5. [17]    M. Tobaiqy ''et al.'', “Therapeutic management of patients with COVID-19: a systematic review,” ''Infect. Prev. Pract.'', vol. 2, no. 3, p. 100061, 2020, doi: 10.1016/j.infpip.2020.100061. [18]    J. M. Cots, J. Alós, M. Bárcena, and X. Boleda, “Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID- 19 . The COVID-19 resource centre is hosted on Elsevier Connect , the company ’ s public news and information,” no. January, 2020. [19]    X. Xu ''et al.'', “Effective treatment of severe COVID-19 patients with tocilizumab,” ''Proc. Natl. Acad. Sci. U. S. A.'', vol. 117, no. 20, pp. 10970–10975, 2020, doi: 10.1073/pnas.2005615117. [20]    D. M. G. Halpin, D. Singh, and R. M. Hadfield, “Inhaled corticosteroids and COVID-19: A systematic review and clinical perspective,” ''Eur. Respir. J.'', vol. 55, no. 5, 2020, doi: 10.1183/13993003.01009-2020. [21]    C. B. Bårnes and C. S. Ulrik, “Asthma and adherence to inhaled corticosteroids: Current status and future perspectives,” ''Respir. Care'', vol. 60, no. 3, pp. 455–468, 2015, doi: 10.4187/respcare.03200. [22]    The Lancet Respiratory Medicine, “Reflecting on World Asthma Day in the era of COVID-19,” ''Lancet Respir. Med.'', vol. 8, no. 5, p. 423, 2020, doi: 10.1016/S2213-2600(20)30184-3. [23]    G. Amaral ''et al.'', “Inhaled Corticosteroids and the Risk of Pneumonia in people with Asthma: A case control study,” ''J. Petrol.'', vol. 369, no. 1, pp. 1689–1699, 2013, doi: 10.1017/CBO9781107415324.004. [24]    N. Veronese ''et al.'', “COVID-19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency,” ''J. Endocrinol. Invest.'', vol. 7, no. April, pp. 1–3, 2020, doi: 10.1007/s40618-020-01266-w. == Additional information == === Acknowledgements === Any people, organisations, or funding sources that you would like to thank. === Competing interests === Any conflicts of interest that you would like to declare. Otherwise, a statement that the authors have no competing interest. === Ethics statement === An ethics statement, if appropriate, on any animal or human research performed should be included here or in the methods section. r8cbw5izbs4hpmxt1geov43016ggbtg 10 283980 2408229 2406479 2022-07-20T22:40:15Z OhanaUnited 18921 remove doc wikitext text/x-wiki {{paid|employer=the [[WikiJournal User Group]]|some=true|additional=A description of the technical editor role's activties, procedures and funding can be seen [[WikiJournal User Group/Technical editors|here]].|demo=<noinclude>2</noinclude>}} dkca61i1e6w8biky8l11eb5q5m9pufa 2408230 2408229 2022-07-20T22:40:36Z OhanaUnited 18921 Undo revision 2408229 by [[Special:Contributions/OhanaUnited|OhanaUnited]] ([[User talk:OhanaUnited|talk]]) wikitext text/x-wiki {{paid|employer=the [[WikiJournal User Group]]|some=true|additional=A description of the technical editor role's activties, procedures and funding can be seen [[WikiJournal User Group/Technical editors|here]].|demo=<noinclude>2</noinclude>}} <noinclude>{{doc}}</noinclude> 5a2vpvj3whs7fznpr8becr0rgj49nnq 2408236 2408230 2022-07-20T23:14:47Z OhanaUnited 18921 reword wikitext text/x-wiki In accordance with the Wikimedia Foundation's [[foundation:Terms of Use]], I disclose that I am an independent contractor who has a contract with [[WikiJournal User Group]] from {{{start|May 2020}}} to {{{end|present}}} and receive compensation for [[WikiJournal User Group/Technical editors|technical editor]] contributions thereof. 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All other edits performed outside of this scope are done in an unpaid, voluntary capacity and do not reflect WikiJournal User Group. <noinclude>{{doc}}</noinclude> h1r9zpc20ohmxfxxeayioeph65akp5m 10 283981 2408253 2395776 2022-07-21T01:50:51Z Evolution and evolvability 922352 /* Usage */ start and end parameters wikitext text/x-wiki {{Documentation subpage}} <!-- Categories and interwikis go at the bottom of this page. --> A user template for [[WikiJournal_User_Group/Technical_editors|WikiJournal technical editors]] == Usage == Simply include <code><nowiki>{{Technical editor}}</nowiki></code> on [[Special:MyPage|your userpage]]. To specify a start or end time, use <code><nowiki>{{Technical editor|start=Jan 2022|end=April 2023}}</nowiki></code> <includeonly> <!-- Categories and interwikis go here: --> [[category:WikiJournal formatting templates]] </includeonly> fr1fojt0r36cdplf5n58nl4lua8p0gh 2 283996 2408314 2395938 2022-07-21T05:56:31Z Jtwsaddress42 234843 wikitext text/x-wiki {{delete| request by original author. page obsolete }} 1a1batipbfpg29na8svdsl0j6rb8g0r 2 284273 2408284 2398551 2022-07-21T05:08:20Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite AV media | last1= Buckley Jr. | first1= William F. | last2= Ali | first2= Muhummad | year= 1968 | title= Muhammad Ali and the Negro Movement | series= Firing Line with William F. Buckley Jr. | medium= Episode 130, Recorded on December 12, 1968 | publisher= Hoover Institution Archives | publication-date= January 25, 2017 | url= https://www.youtube.com/watch?v=NxpuT1SNurU }} [[File:High-contrast-camera-video.svg|24px|video]] (0:52:03) {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} * {{cite AV media | last1= Buckley Jr. | first1= William F. | last2= Reagan | first2= Ronald | year= 1980 | title= Presidential Hopeful: Ronald Reagan | series= Firing Line with William F. Buckley Jr. | medium= Episode 401, Recorded on January 14, 1980 | publisher= Hoover Institution Archives | publication-date= February 1, 2017 | url= https://www.youtube.com/watch?v=9DvmLMUfGss }} [[File:High-contrast-camera-video.svg|24px|video]] (0:59:18) 2d6bcbz6d0bxpcvnxl1gxsqh1xr6ldc 2 285078 2408218 2404387 2022-07-20T20:21:49Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last1= Nübler-Jung | first1= Katharina | last2= Arendt | first2= Detlev | date= 1994a | title= Is ventral in insects dorsal in vertebrates? : A history of embryological arguments favouring axis inversion in chordate ancestors | journal= Rouxs Archives of Developmental Biology | volume= 203 | number= 7–8 | pages= 357–366 | doi= 10.1007/BF00188683 | pmid= 28305940 | s2cid= 21250472 | url= https://pubmed.ncbi.nlm.nih.gov/28305940/ }} * {{cite journal | last1= Nübler-Jung | first1= Katharina | last2= Arendt | first2= Detlev | year=1994b | date= September 1, 1994 | title= Inversion of dorsoventral axis? | journal= Nature | volume= 371 | number= 6492 | pages= 461–478 | doi= 10.1038/371026a0 | pmid= 072524 | bibcode= 1994Natur.371...26A | s2cid= 33780610 | url= https://www.nature.com/articles/371026a0.pdf }} * {{cite journal | last1= Nübler-Jung | first1= Katharina | last2= Arendt | first2= Detlev | year= 1996 | publication-date= March 1996 | title= Common ground plans in early brain development in mice and flies | journal= BioEssays | volume= 18 | number= 3 | pages= 255–259 | doi= 10.1002/bies.950180314 | pmid= 8867740 | url= https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.950180314 }} 4f1cliqxmdcvb2bx1z59thpzwxt38zr 2 285087 2408250 2404399 2022-07-21T01:48:57Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last1= Pasumansky, | first1= Lubov | last2= Goralski | first2= Christian T. | last3= Singaram | first3= Bakthan | year= 2006 | title= Lithium Aminoborohydrides: Powerful, Selective, Air-Stable Reducing Agents | journal= Organic Process Research & Development | volume= 10 | number= 5 | pages= 959-970 | publication-date= September 2006 | doi= 10.1021/op0600759 | url= https://pubs.acs.org/doi/10.1021/op0600759 }} * {{cite journal | last1= Pasumansky | first1= Lubov | last2= Collins | first2= Christopher J. | last3= Pratt | first3= Lawrence M. | last4= Nguỹên | first4= Ngân Vǎn | last5= Ramachandran | first5= B. | last6= Singaram | first6= Bakthan | year= 2007 | title= Solvent and Temperature Effects On The Reduction And Amination Reactions Of Electrophiles By Lithium Dialkylaminoborohydrides | journal= The Journal Of Organic Chemistry | volume= 72 | number= 3 | pages= 971-976 | publication-date= February 2, 2007 | pmid= 17253818 | doi= 10.1021/jo062154o | url= https://pubs.acs.org/doi/10.1021/jo062154o }} * {{cite journal | last1= Pasumansky | first1= Lubov | last2= Haddenham | first2= Dustin | last3= Clary | first3= Jacob W. | last4= Fisher | first4= Gary B. | last5= Goralski | first5= Christian T. | last6= Singaram | first6= Bakthan | year= 2008 | title= Lithium Aminoborohydrides 16. Synthesis And Reactions Of Monomeric And Dimeric Aminoboranes | journal= The Journal of Organic Chemistry | volume= 73 | number= 5 | pages= 1898-1905 | publication-date= March 7, 2008 | pmid= 18215062 | doi= 10.1021/jo702271c | url= https://pubs.acs.org/doi/10.1021/jo702271c }} hansjjp7kcb5kcty8sne6dpjwctlfrg 0 285113 2408273 2407787 2022-07-21T04:35:20Z Marshallsumter 311529 /* STS-43 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] dcmxwl2rmt2ogui66d0465jc9gn2p6w 2408274 2408273 2022-07-21T04:38:37Z Marshallsumter 311529 /* STS-19 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle Discovery. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] f4ls6u81pb1tl3mejqmj6zql099mk2m 2408278 2408274 2022-07-21T04:51:01Z Marshallsumter 311529 /* STS-19 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] pde5qx0e2dqeshltj109vaqbpl4w8rk 2408295 2408278 2022-07-21T05:23:48Z Marshallsumter 311529 /* STS-7 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle Challenger. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] anp360n4y8zwjst0b2nfn0rcopqn53o 2408296 2408295 2022-07-21T05:25:00Z Marshallsumter 311529 /* STS-7 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] 8sm1s8wma3jzkivmshkjc2cwvttsw3v 2408297 2408296 2022-07-21T05:25:24Z Marshallsumter 311529 /* STS-8 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] cue1wigzucllh10onw3i9rrvyqpqaem 2408308 2408297 2022-07-21T05:41:00Z Marshallsumter 311529 /* STS-13 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] itjr68x5ny4drubt01d69b30qw4nebg 2408322 2408308 2022-07-21T06:09:29Z Marshallsumter 311529 /* STS-19 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-21== STS-51-D was the 16th flight of NASA's Space Shuttle program, and the fourth flight of Space Shuttle ''Discovery''.<ref name=PressKitit51D>{{cite web |url=http://www.shuttlepresskit.com/STS-51D/STS51D.pdf|title=STS-51D Press Kit|author=NASA|accessdate=December 16, 2009}}</ref> ''Discovery''s other mission payloads included the Continuous Flow Electrophoresis System III (CFES-III), which was flying for sixth time; two Shuttle Student Involvement Program (SSIP) experiments; the American Flight Echo-cardiograph (AFE); two Getaway specials (GASs); a set of Phase Partitioning Experiments (PPE); an astronomical photography verification test; various medical experiments; and "Toys in Space", an informal study of the behavior of simple toys in a microgravity environment, with the results being made available to school students upon the shuttle's return.<ref>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-51D.html|title=STS-51D|publisher=NASA|accessdate=January 16, 2018|date=February 18, 2010}}</ref> ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] 4snzo76lhsm1a5hikiobwlxmuog372d 2408330 2408322 2022-07-21T06:21:35Z Marshallsumter 311529 /* STS-21 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-21== STS-51-D was the 16th flight of NASA's Space Shuttle program, and the fourth flight of Space Shuttle ''Discovery''.<ref name=PressKitit51D>{{cite web |url=http://www.shuttlepresskit.com/STS-51D/STS51D.pdf|title=STS-51D Press Kit|author=NASA|accessdate=December 16, 2009}}</ref> ''Discovery''s other mission payloads included the Continuous Flow Electrophoresis System III (CFES-III), which was flying for sixth time; two Shuttle Student Involvement Program (SSIP) experiments; the American Flight Echo-cardiograph (AFE); two Getaway specials (GASs); a set of Phase Partitioning Experiments (PPE); an astronomical photography verification test; various medical experiments; and "Toys in Space", an informal study of the behavior of simple toys in a microgravity environment, with the results being made available to school students upon the shuttle's return.<ref>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-51D.html|title=STS-51D|publisher=NASA|accessdate=January 16, 2018|date=February 18, 2010}}</ref> ==STS-22== [[Image:STS-51-B crew in Spacelab.jpg|thumb|right|250px|Space Transportation System-17, Spacelab 3, Overmyer, Lind, van den Berg, and Thornton are in the Spacelab Module LM1 during flight. Credit: STS-22 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|upright=1.0|left|250px|Launch of STS-51B is shown. Credit:NASA.{{tlx|free media}}]] STS-51B was the 17th flight of NASA's Space Shuttle program, and the seventh flight of Space Shuttle ''Challenger''. STS-51B was the second flight of the European Space Agency (ESA)'s Spacelab pressurized module, and the first with the Spacelab module in a fully operational configuration. Spacelab's capabilities for multi-disciplinary research in microgravity were successfully demonstrated. The gravity gradient attitude of the orbiter proved quite stable, allowing the delicate experiments in materials processing and fluid mechanics to proceed normally. The crew operated around the clock in two 12-hour shifts. Two squirrel monkeys and 24 Brown rats were flown in special cages,<ref>|url=https://web.archive.org/web/20110719061203/http://lis.arc.nasa.gov/lis/Programs/STS/STS_51B/STS_51B.html|date=July 19, 2011</ref> the second time American astronauts flew live non-human mammals aboard the shuttle. The crew members in orbit were supported 24 hours a day by a temporary Payload Operations Control Center, located at the Johnson Space Center. On the mission, Spacelab carried 15 primary experiments, of which 14 were successfully performed. Two Getaway Special (GAS) experiments required that they be deployed from their canisters, a first for the program. These were NUSAT (Northern Utah Satellite) and GLOMR (Global Low Orbiting Message Relay satellite). NUSAT deployed successfully, but GLOMR did not deploy, and was returned to Earth. {{clear}} ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] 44ugdy68u388d7jc4veuznzag85w81t 2408358 2408330 2022-07-21T06:49:11Z Marshallsumter 311529 /* STS-43 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-21== STS-51-D was the 16th flight of NASA's Space Shuttle program, and the fourth flight of Space Shuttle ''Discovery''.<ref name=PressKitit51D>{{cite web |url=http://www.shuttlepresskit.com/STS-51D/STS51D.pdf|title=STS-51D Press Kit|author=NASA|accessdate=December 16, 2009}}</ref> ''Discovery''s other mission payloads included the Continuous Flow Electrophoresis System III (CFES-III), which was flying for sixth time; two Shuttle Student Involvement Program (SSIP) experiments; the American Flight Echo-cardiograph (AFE); two Getaway specials (GASs); a set of Phase Partitioning Experiments (PPE); an astronomical photography verification test; various medical experiments; and "Toys in Space", an informal study of the behavior of simple toys in a microgravity environment, with the results being made available to school students upon the shuttle's return.<ref>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-51D.html|title=STS-51D|publisher=NASA|accessdate=January 16, 2018|date=February 18, 2010}}</ref> ==STS-22== [[Image:STS-51-B crew in Spacelab.jpg|thumb|right|250px|Space Transportation System-17, Spacelab 3, Overmyer, Lind, van den Berg, and Thornton are in the Spacelab Module LM1 during flight. Credit: STS-22 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|upright=1.0|left|250px|Launch of STS-51B is shown. Credit:NASA.{{tlx|free media}}]] STS-51B was the 17th flight of NASA's Space Shuttle program, and the seventh flight of Space Shuttle ''Challenger''. STS-51B was the second flight of the European Space Agency (ESA)'s Spacelab pressurized module, and the first with the Spacelab module in a fully operational configuration. Spacelab's capabilities for multi-disciplinary research in microgravity were successfully demonstrated. The gravity gradient attitude of the orbiter proved quite stable, allowing the delicate experiments in materials processing and fluid mechanics to proceed normally. The crew operated around the clock in two 12-hour shifts. Two squirrel monkeys and 24 Brown rats were flown in special cages,<ref>|url=https://web.archive.org/web/20110719061203/http://lis.arc.nasa.gov/lis/Programs/STS/STS_51B/STS_51B.html|date=July 19, 2011</ref> the second time American astronauts flew live non-human mammals aboard the shuttle. The crew members in orbit were supported 24 hours a day by a temporary Payload Operations Control Center, located at the Johnson Space Center. On the mission, Spacelab carried 15 primary experiments, of which 14 were successfully performed. Two Getaway Special (GAS) experiments required that they be deployed from their canisters, a first for the program. These were NUSAT (Northern Utah Satellite) and GLOMR (Global Low Orbiting Message Relay satellite). NUSAT deployed successfully, but GLOMR did not deploy, and was returned to Earth. {{clear}} ==STS-23== [[Image:STS-51-G Morelos 1 deployment.jpg|thumb|right|250px|Mexico's Morelos satellite deploys from Discovery's payload bay. Credit: NASA STS-23 crew.{{tlx|free media}}]] [[Image:STS-51-G Spartan 1.jpg|thumb|left|250px|Spartan 1 is shown after deployment on STS-51-G. Credit: NASA STS-23 crew.{{tlx|free media}}]] STS-51-G was the 18th flight of NASA's Space Shuttle program, and the fifth flight of Space Shuttle ''Discovery''. The SPARTAN-1 (Shuttle Pointed Autonomous Research Tool for AstroNomy) a deployable/retrievable carrier module, was designed to be deployed from the orbiter and fly free in space before being retrieved. SPARTAN-1 included {{cvt|140|kg}} of astronomy experiments. It was deployed and operated successfully, independent of the orbiter, before being retrieved. ''Discovery'' furthermore carried an experimental materials-processing furnace, two French biomedical experiments (French Echocardiograph Experiment (FEE) and French Postural Experiment (FPE)),<ref name=SF51G>{{cite web|title=STS-51G|url=http://spacefacts.de/mission/english/sts-51g.htm|publisher=Spacefacts|accessdate=23 January 2021}}</ref> and six Getaway Special (GAS) experiments, which were all successfully performed, although the GO34 Getaway Special shut down prematurely. This mission was also the first flight test of the OEX advanced autopilot which gave the orbiter capabilities above and beyond those of the baseline system. The mission's final payload element was a High Precision Tracking Experiment (HPTE) for the Strategic Defense Initiative (SDI) (nicknamed "Star Wars"); the HPTE successfully deployed on orbit 64. {{clear}} ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] 5ozh0ed879w2m694fp1a71sm2b8j958 2408375 2408358 2022-07-21T07:00:51Z Marshallsumter 311529 /* STS-23 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-21== STS-51-D was the 16th flight of NASA's Space Shuttle program, and the fourth flight of Space Shuttle ''Discovery''.<ref name=PressKitit51D>{{cite web |url=http://www.shuttlepresskit.com/STS-51D/STS51D.pdf|title=STS-51D Press Kit|author=NASA|accessdate=December 16, 2009}}</ref> ''Discovery''s other mission payloads included the Continuous Flow Electrophoresis System III (CFES-III), which was flying for sixth time; two Shuttle Student Involvement Program (SSIP) experiments; the American Flight Echo-cardiograph (AFE); two Getaway specials (GASs); a set of Phase Partitioning Experiments (PPE); an astronomical photography verification test; various medical experiments; and "Toys in Space", an informal study of the behavior of simple toys in a microgravity environment, with the results being made available to school students upon the shuttle's return.<ref>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-51D.html|title=STS-51D|publisher=NASA|accessdate=January 16, 2018|date=February 18, 2010}}</ref> ==STS-22== [[Image:STS-51-B crew in Spacelab.jpg|thumb|right|250px|Space Transportation System-17, Spacelab 3, Overmyer, Lind, van den Berg, and Thornton are in the Spacelab Module LM1 during flight. Credit: STS-22 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|upright=1.0|left|250px|Launch of STS-51B is shown. Credit:NASA.{{tlx|free media}}]] STS-51B was the 17th flight of NASA's Space Shuttle program, and the seventh flight of Space Shuttle ''Challenger''. STS-51B was the second flight of the European Space Agency (ESA)'s Spacelab pressurized module, and the first with the Spacelab module in a fully operational configuration. Spacelab's capabilities for multi-disciplinary research in microgravity were successfully demonstrated. The gravity gradient attitude of the orbiter proved quite stable, allowing the delicate experiments in materials processing and fluid mechanics to proceed normally. The crew operated around the clock in two 12-hour shifts. Two squirrel monkeys and 24 Brown rats were flown in special cages,<ref>|url=https://web.archive.org/web/20110719061203/http://lis.arc.nasa.gov/lis/Programs/STS/STS_51B/STS_51B.html|date=July 19, 2011</ref> the second time American astronauts flew live non-human mammals aboard the shuttle. The crew members in orbit were supported 24 hours a day by a temporary Payload Operations Control Center, located at the Johnson Space Center. On the mission, Spacelab carried 15 primary experiments, of which 14 were successfully performed. Two Getaway Special (GAS) experiments required that they be deployed from their canisters, a first for the program. These were NUSAT (Northern Utah Satellite) and GLOMR (Global Low Orbiting Message Relay satellite). NUSAT deployed successfully, but GLOMR did not deploy, and was returned to Earth. {{clear}} ==STS-23== [[Image:STS-51-G Morelos 1 deployment.jpg|thumb|right|250px|Mexico's Morelos satellite deploys from Discovery's payload bay. Credit: NASA STS-23 crew.{{tlx|free media}}]] [[Image:STS-51-G Spartan 1.jpg|thumb|left|250px|Spartan 1 is shown after deployment on STS-51-G. Credit: NASA STS-23 crew.{{tlx|free media}}]] STS-51-G was the 18th flight of NASA's Space Shuttle program, and the fifth flight of Space Shuttle ''Discovery''. The SPARTAN-1 (Shuttle Pointed Autonomous Research Tool for AstroNomy) a deployable/retrievable carrier module, was designed to be deployed from the orbiter and fly free in space before being retrieved. SPARTAN-1 included {{cvt|140|kg}} of astronomy experiments. It was deployed and operated successfully, independent of the orbiter, before being retrieved. ''Discovery'' furthermore carried an experimental materials-processing furnace, two French biomedical experiments (French Echocardiograph Experiment (FEE) and French Postural Experiment (FPE)),<ref name=SF51G>{{cite web|title=STS-51G|url=http://spacefacts.de/mission/english/sts-51g.htm|publisher=Spacefacts|accessdate=23 January 2021}}</ref> and six Getaway Special (GAS) experiments, which were all successfully performed, although the GO34 Getaway Special shut down prematurely. This mission was also the first flight test of the OEX advanced autopilot which gave the orbiter capabilities above and beyond those of the baseline system. The mission's final payload element was a High Precision Tracking Experiment (HPTE) for the Strategic Defense Initiative (SDI) (nicknamed "Star Wars"); the HPTE successfully deployed on orbit 64. {{clear}} ==STS-24== STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] ry7sbwrdxm1i43vrqdiio7z3spjclsy 2408386 2408375 2022-07-21T07:13:43Z Marshallsumter 311529 /* STS-24 */ wikitext text/x-wiki <imagemap> File:Space station size comparison.svg|270px|thumb|[[File:interactive icon.svg|left|18px|link=|The image above contains clickable links|alt=The image above contains clickable links]] Size comparisons between current and past space stations as they appeared most recently. Solar panels in blue, heat radiators in red. Note that stations have different depths not shown by silhouettes. Credit: [[w:user:Evolution and evolvability|Evolution and evolvability]].{{tlx|free media}} rect 0 0 550 420 [[International Space Station]] rect 550 0 693 420 [[Tiangong Space Station]] rect 0 420 260 700 [[Mir]] rect 260 420 500 700 [[Skylab]] rect 500 420 693 700 [[Tiangong-2]] rect 0 700 160 921 [[Salyut 1]] rect 160 700 280 921 [[Salyut 2]] rect 280 700 420 921 [[Salyut 4]] rect 420 700 550 921 [[Salyut 6]] rect 550 700 693 921 [[Salyut 7]] </imagemap> '''Def.''' a "manned [crewed] artificial satellite designed for long-term habitation, research, etc."<ref name=SpaceStationWikt>{{ cite book |author=[[wikt:User:SemperBlotto|SemperBlotto]] |title=space station |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=20 June 2005 |url=https://en.wiktionary.org/wiki/space_station |accessdate=6 July 2022 }}</ref> is called a '''space station'''. '''Def.''' "a space station, generally constructed for one purpose, that orbits a celestial body such as a planet, asteroid, or star"<ref name=OrbitalPlatform>{{ cite web |author=Roberts |title=Orbital platform |publisher=Roberts Space Industries |location= |date=2021 |url=https://robertsspaceindustries.com/galactapedia/article/box5vnAx5w-orbital-platform |accessdate=6 July 2022 }}</ref> is called an '''orbital platform'''. {{clear}} ==International Space Station== [[Image:STS-134 International Space Station after undocking.jpg|thumb|right|250px|The International Space Station is featured in this image photographed by an STS-134 crew member on the space shuttle Endeavour after the station and shuttle began their post-undocking relative separation. Credit: NASA.{{tlx|free media}}]] [[Image:ISS August06.jpg|thumb|left|250px|The Space Shuttle Endeavor crew captured this shot of the International Space Station (ISS) against the backdrop of Planet Earth. Credit: NASA.{{tlx|free media}}]] [[Image:539956main ISS466.jpg|thumb|right|250px|The MISSE are usually loaded on the outside of International Space Station. The inset image shows where. Credit: NASA.{{tlx|fairuse}}]] [[Image:STS-134 the starboard truss of the ISS with the newly-installed AMS-02.jpg|thumb|left|250px|In this image, the Alpha Magnetic Spectrometer-2 (AMS-02) is visible at center left on top of the starboard truss of the International Space Station. Credit: STS-134 crew member and NASA.{{tlx|free media}}]] [[Image:Nasasupports.jpg|thumb|right|250px|This is a computer-generated image of the Extreme Universe Space Observatory (EUSO) as part of the Japanese Experiment Module (JEM) on the International Space Station (ISS). Credit: JEM-EUSO, Angela Olinto.{{tlx|fairuse}}]] [[Image:BBND1.jpg|thumb|right|250px|This image shows a Bonner Ball Neutron Detector which is housed inside the small plastic ball when the top is put back on. Credit: NASA.{{tlx|free media}}]] On the right is the International Space Station after the undocking of STS-134 Space Shuttle. The Space Shuttle Endeavor crew captured this shot [on the left] of the International Space Station (ISS) against the backdrop of Planet Earth. "Since 2001, NASA and its partners have operated a series of flight experiments called Materials International Space Station Experiment, or MISSE [on the second right]. The objective of MISSE is to test the stability and durability of materials and devices in the space environment."<ref name=Sheldon>{{ cite book |author=Sheldon |title=Materials: Out of This World |publisher=NASA News |location=Washington DC USA |date=April 29, 2011 |url=http://spacestationinfo.blogspot.com/2011_04_01_archive.html |accessdate=2014-01-08 }}</ref> The '''Alpha Magnetic Spectrometer''' on the second left is designed to search for various types of unusual matter by measuring cosmic rays. The '''Extreme Universe Space Observatory''' ('''EUSO''') [on the third right] is the first Space mission concept devoted to the investigation of cosmic rays and neutrinos of [[w:Ultra-high-energy cosmic ray|extreme energy]] ({{nowrap|E > {{val|5|e=19|u=eV}}}}). Using the Earth's atmosphere as a giant detector, the detection is performed by looking at the streak of [[w:fluorescence|fluorescence]] produced when such a particle interacts with the Earth's atmosphere. The Space Environment Data Acquisition equipment-Attached Payload (SEDA-AP) aboard the Kibo (International Space Station module) measures neutrons, plasma, heavy ions, and high-energy light particles in ISS orbit. On the lower right is a Bonner Ball Neutron Detector "BBND ... determined that galactic cosmic rays were the major cause of secondary neutrons measured inside ISS. The neutron energy spectrum was measured from March 23, 2001 through November 14, 2001 in the U.S. Laboratory Module of the ISS. The time frame enabled neutron measurements to be made during a time of increased solar activity (solar maximum) as well as observe the results of a solar flare on November 4, 2001."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> "Bonner Ball Neutron Detector (BBND) [shown with its cap off] measures neutron radiation (low-energy, uncharged particles) which can deeply penetrate the body and damage blood forming organs. Neutron radiation is estimated to be 20 percent of the total radiation on the International Space Station (ISS). This study characterizes the neutron radiation environment to develop safety measures to protect future ISS crews."<ref name=Choy>{{ cite book |author=Tony Choy |title=Bonner Ball Neutron Detector (BBND) |publisher=NASA |location=Johnson Space Center, Human Research Program, Houston, TX, United States |date=July 25, 2012 |url=http://www.nasa.gov/mission_pages/station/research/experiments/BBND.html |accessdate=2012-08-17 }}</ref> Six BBND detectors were distributed around the International Space Station (ISS) to allow data collection at selected points. "The six BBND detectors provided data indicating how much radiation was absorbed at various times, allowing a model of real-time exposure to be calculated, as opposed to earlier models of passive neutron detectors which were only capable of providing a total amount of radiation received over a span of time. Neutron radiation information obtained from the Bonner Ball Neutron Detector (BBND) can be used to develop safety measures to protect crewmembers during both long-duration missions on the ISS and during interplanetary exploration."<ref name=Choy/> "The Bonner Ball Neutron Detector (BBND) developed by Japan Aerospace and Exploration Agency (JAXA) was used inside the International Space Station (ISS) to measure the neutron energy spectrum. It consisted of several neutron moderators enabling the device to discriminate neutron energies up to 15 MeV (15 mega electron volts). This BBND characterized the neutron radiation on ISS during Expeditions 2 and 3."<ref name=Choy/> "BBND results show the overall neutron environment at the ISS orbital altitude is influenced by highly energetic galactic cosmic rays, except in the South Atlantic Anomaly (SAA) region where protons trapped in the Earth's magnetic field cause a more severe neutron environment. However, the number of particles measured per second per square cm per MeV obtained by BBND is consistently lower than that of the precursor investigations. The average dose-equivalent rate observed through the investigation was 3.9 micro Sv/hour or about 10 times the rate of radiological exposure to the average US citizen. In general, radiation damage to the human body is indicated by the amount of energy deposited in living tissue, modified by the type of radiation causing the damage; this is measured in units of Sieverts (Sv). The background radiation dose received by an average person in the United States is approximately 3.5 milliSv/year. Conversely, an exposure of 1 Sv can result in radiation poisoning and a dose of five Sv will result in death in 50 percent of exposed individuals. The average dose-equivalent rate observed through the BBND investigation is 3.9 micro Sv/hour, or about ten times the average US surface rate. The highest rate, 96 microSv/hour was observed in the SAA region."<ref name=Choy/> "The November 4, 2001 solar flare and the associated geomagnetic activity caused the most severe radiation environment inside the ISS during the BBND experiment. The increase of neutron dose-equivalent due to those events was evaluated to be 0.19mSv, which is less than 1 percent of the measured neutron dose-equivalent measured over the entire 8-month period."<ref name=Choy/> {{clear}} ==Mir== [[Image:Mir Space Station viewed from Endeavour during STS-89.jpg|thumb|right|250px|Approach view is of the Mir Space Station viewed from Space Shuttle Endeavour during the STS-89 rendezvous. Credit: NASA.{{tlx|free media}}]] In the image on the right, a Progress cargo ship is attached on the left, a Soyuz manned spacecraft attached on the right. Mir is seen on the right from Space Shuttle Endeavour during STS-89 (28 January 1998). Mir was a space station that operated in low Earth orbit from 1986 to 2001, operated by the Soviet Union and later by Russia. Mir was the first modular space station and was assembled in orbit from 1986 to 1996. It had a greater mass than any previous spacecraft. At the time it was the largest artificial satellite in orbit, succeeded by the International Space Station (ISS) after Mir's orbit decayed. ''Mir'' was the first continuously inhabited long-term research station in orbit and held the record for the longest continuous human presence in space at 3,644 days, until it was surpassed by the ISS on 23 October 2010.<ref name=Jackman>{{cite journal|last=Jackman|first=Frank|title=ISS Passing Old Russian Mir In Crewed Time|url=http://www.aviationweek.com/aw/generic/story_channel.jsp?channel=space&id=news/asd/2010/10/28/11.xml|Journal=Aviation Week|date=29 October 2010}}</ref> The first module of the station, known as the Mir Core Module or base block, was launched in 1986 and followed by six further modules. Proton rockets were used to launch all of its components except for the Mir Docking Module, which was installed by US Space Shuttle mission STS-74 in 1995. When complete, the station consisted of seven pressurised modules and several unpressurised components. Power was provided by several photovoltaic arrays attached directly to the modules. The station was maintained at an orbit between {{convert|296|km|mi|0|abbr=on}} and {{convert|421|km|mi|0|abbr=on}} altitude and travelled at an average speed of 27,700&nbsp;km/h (17,200&nbsp;mph), completing 15.7 orbits per day.<ref name="MirBIS">{{cite book|title=The History of Mir 1986–2000|publisher=British Interplanetary Society|{{isbn|978-0-9506597-4-9}}|editor=Hall, R.|url=https://archive.org/details/historyofmir19860000unse |date=February 2021}}</ref><ref name="FinalBIS">{{cite book|title=Mir: The Final Year|publisher=British Interplanetary Society|{{isbn|978-0-9506597-5-6}}|editor=Hall, R. |date=February 2021}}</ref><ref name="OrbitCalc">{{cite web|title=Orbital period of a planet|publisher=CalcTool|accessdate=12 September 2010|url=https://web.archive.org/web/20191112095042/http://www.calctool.org/CALC/phys/astronomy/planet_orbit }}</ref> {{clear}} ==Polar Satellite 4== [[Image:PSLV C45 EMISAT campaign 09.jpg|right|thumb|375x375px|Third and fourth stages of PSLV-C45. Credit: Indian Space Research Organisation.{{tlx|free media}}]] PS4 has carried hosted payloads like AAM on PSLV-C8,<ref name=":6">{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C8/files/assets/common/downloads/publication.pdf|title=PSLV C8 / AGILE brochure}}</ref> Luxspace (Rubin 9.1)/(Rubin 9.2) on PSLV-C14<ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/flipping_book/PSLV-C14/files/assets/common/downloads/publication.pdf|title=PSLV C14/Oceansat-2 brochure}}</ref> and mRESINS on PSLV-C21.<ref>{{cite web |url=https://www.dos.gov.in/sites/default/files/flipping_book/Space%20India%20July%2012-Aug%2013/files/assets/common/downloads/Space%20India%20July%2012-Aug%2013.pdf|title=Space-India July 2012 to August 2013 }}</ref> PS4 is being augmented to serve as a long duration orbital platform after completion of its primary mission. PS4 Orbital Platform (PS4-OP) will have its own power supply, telemetry package, data storage and attitude control for hosted payloads.<ref>{{cite web|url=http://www.unoosa.org/documents/pdf/copuos/stsc/2019/tech-55E.pdf|title=Opportunities for science experiments in the fourth stage of India's PSLV|date=21 February 2019}}</ref><ref>{{cite web|url=https://www.isro.gov.in/sites/default/files/orbital_platform-_ao.pdf|title=Announcement of Opportunity (AO) for Orbital platform: an avenue for in-orbit scientific experiments|date=15 June 2019}}</ref><ref>{{cite web|url=https://timesofindia.indiatimes.com/india/2-days-after-space-station-news-isro-calls-for-docking-experiments-on-pslv-stage-4/articleshow/69800354.cms|title=2 days after Space Station news, Isro calls for "docking experiments" on PSLV stage-4|first=Chethan|last=Kumar|work=The Times of India|accessdate=23 February 2020}}</ref> On PSLV-C37 and PSLV-C38 campaigns,<ref>{{Cite web |title=''In-situ'' observations of rocket burn induced modulations of the top side ionosphere using the IDEA payload on-board the unique orbiting experimental platform (PS4) of the Indian Polar Orbiting Satellite Launch Vehicle mission - ISRO |url=https://www.isro.gov.in/situ-observations-of-rocket-burn-induced-modulations-of-top-side-ionosphere-using-idea-payload-board |accessdate=2022-06-27 |website=www.isro.gov.in |language=en}}</ref> as a demonstration PS4 was kept operational and monitored for over ten orbits after delivering spacecraft.<ref>{{cite web |title=Department of Space Annual Report 2017-18|url=https://web.archive.org/web/20180213093132/https://www.isro.gov.in/sites/default/files/article-files/node/9805/annualreport2017-18.pdf }}</ref><ref name=Singh>{{cite web |url=https://timesofindia.indiatimes.com/india/in-a-first-isro-will-make-dead-rocket-stage-alive-in-space-for-experiments/articleshow/67067817.cms|title=In a first, ISRO will make dead rocket stage "alive" in space for experiments|first=Surendra|last=Singh|work=The Times of India|date=16 December 2018|accessdate=23 February 2020}}</ref><ref name=Rajasekhar>{{cite web|url=https://www.deccanchronicle.com/science/science/200617/isro-to-lower-rockets-altitude.html|title=Isro to lower rocket's altitude|last=rajasekhar|first=pathri|publisher=Deccan Chronicle|date=2017-06-20|accessdate=23 February 2020}}</ref> PSLV-C44 was the first campaign where PS4 functioned as independent orbital platform for short duration as there was no on-board power generation capacity.<ref name=Rajwi>{{cite news|last=Rajwi|first=Tiki |url=https://www.thehindu.com/news/national/kerala/pslv-lift-off-with-added-features/article25981654.ece|title=PSLV lift-off with added features|date=2019-01-12|newspaper=The Hindu|issn=0971-751X|accessdate=23 February 2020}}</ref> It carried KalamSAT-V2 as a fixed payload, a 1U cubesat by Space Kidz India based on Interorbital Systems kit.<ref>{{cite web|title=PSLV-C44 - ISRO |url=https://www.isro.gov.in/launcher/pslv-c44|accessdate=26 June 2020|website=isro.gov.in}}</ref><ref>{{cite web |title=Congratulations to ISRO and SpaceKidzIndia on getting their CubeSat into orbit! The students modified their IOS CubeSat kit, complete w/ their own experiments!|author=Interorbital Systems|date=25 January 2019|url=https://twitter.com/interorbital/status/1088526772109422592 }}</ref> On PSLV-C45 campaign, the fourth stage had its own power generation capability as it was augmented with an array of fixed solar cells around PS4 propellant tank.<ref name=Clark>{{cite web |url=https://spaceflightnow.com/2019/04/01/indian-military-satellite-20-more-planet-imaging-cubesats-aboard-successful-pslv-launch/|title=Indian military satellite, 20 more Planet imaging CubeSats launched by PSLV|last=Clark|first=Stephen|publisher=Spaceflight Now|accessdate=2020-02-23}}</ref> Three payloads hosted on PS4-OP were, Advanced Retarding Potential Analyzer for Ionospheric Studies (ARIS 101F) by IIST,<ref>{{cite web|url=https://www.iist.ac.in/avionics/sudharshan.kaarthik|title=Department of Avionics, R. Sudharshan Kaarthik, Ph.D (Assistant Professor)}}</ref> experimental Automatic identification system (AIS) payload by ISRO and AISAT by Satellize.<ref>{{cite web|url=https://satellize.com/index.php/exseed-sat-2/|title=Exseed Sat-2|publisher=Satellize|accessdate=23 February 2020}}</ref> To function as orbital platform, fourth stage was put in spin-stabilized mode using its RCS thrusters.<ref>{{Cite web |date=16 June 2021 |title=Opportunity for Scientific Experiments on PSLV Upper Stage Orbital Platform |url=https://www.unoosa.org/documents/pdf/psa/hsti/Hyper-Microgravity_Webinar2021/Hyper-Microgravity_Webinar2021/9_RegionalActivities/R._Senan_Hypermicrogravity_ISRO.pdf}}</ref> ==Salyut 1== [[Image:Salyut 1.jpg|thumb|right|250px|Salyut 1 is photographed from the departing Soyuz 11. Credit: [[w:user:Viktor Patsayev|Viktor Patsayev]].{{tlx|fairuse}}]] Salyut 1 (DOS-1) was the world's first space station launched into low Earth orbit by the Soviet Union on April 19, 1971. The Soyuz 11 crew achieved successful hard docking and performed experiments in Salyut 1 for 23 days. Civilian Soviet space stations were internally referred to as DOS (the Russian acronym for "Long-duration orbital station"), although publicly, the Salyut name was used for the first six DOS stations (''Mir'' was internally known as DOS-7).<ref>Portree, David S. F. (March 1995). "Part 2 – Almaz, Salyut, and Mir" . Mir Hardware Heritage . Johnson Space Center Reference Series. NASA. NASA Reference Publication 1357 – via Wikisource.</ref> The astrophysical Orion 1 Space Observatory designed by Grigor Gurzadyan of Byurakan Observatory in Armenia, was installed in Salyut 1. Ultraviolet spectrograms of stars were obtained with the help of a mirror telescope of the Mersenne Three-mirror_anastigmat system and a spectrograph of the Wadsworth system using film sensitive to the far ultraviolet. The dispersion of the spectrograph was 32&nbsp;Å/mm (3.2&nbsp;nm/mm), while the resolution of the spectrograms derived was about 5&nbsp;Å at 2600&nbsp;Å (0.5&nbsp;nm at 260&nbsp;nm). Slitless spectrograms were obtained of the stars ''Vega'' and ''Beta Centauri'' between 2000 and 3800&nbsp;Å (200 and 380&nbsp;nm).<ref name=Gurzadyan>{{cite journal |title=Observed Energy Distribution of α Lyra and β Cen at 2000–3800 Å |journal=Nature |first1=G. A. |last1=Gurzadyan |first2=J. B. |last2=Ohanesyan |volume=239 |issue=5367 |page=90 |date=September 1972 |doi=10.1038/239090a0 |bibcode=1972Natur.239...90G|s2cid=4265702 }}</ref> The telescope was operated by crew member Viktor Patsayev, who became the first man to operate a telescope outside of the Earth's atmosphere.<ref name="Marett-Crosby2013">{{cite book|last=Marett-Crosby|first=Michael|title=Twenty-Five Astronomical Observations That Changed the World: And How To Make Them Yourself|url=https://books.google.com/books?id=0KRSphlvsqgC&pg=PA282|accessdate=2018-04-18|date=2013-06-28|publisher=Springer Science & Business Media|{{isbn|9781461468004}}|page=282 }}</ref> {{clear}} ==Salyut 3== [[Image:Salyut 3 paper model.JPG|thumb|right|250px|Salyut 3 (Almaz 2) Soviet military space station model shows Soyuz 14 docked. Credit: [[c:user:Godai|Godai]].{{tlx|free media}}]] Salyut 3; also known as OPS-2<ref name=Zak>{{cite web|url=http://www.russianspaceweb.com/almaz_ops2.html|title=OPS-2 (Salyut-3)|author=Anatoly Zak|publisher=RussianSpaceWeb.com}}</ref> or Almaz 2<ref name=Portree1995>D.S.F. Portree (March 1995). "Mir Hardware Heritage" (PDF). NASA. Archived from the original (PDF) on 2009-09-07.</ref>) was a Soviet Union space station launched on 25 June 1974. It was the second Almaz military space station, and the first such station to be launched successfully.<ref name=Portree1995/> It was included in the Salyut program to disguise its true military nature.<ref name=Hall>Rex Hall, David Shayler (2003). Soyuz: a universal spacecraft. Springer. p. 459. ISBN 1-85233-657-9.</ref> Due to the military nature of the station, the Soviet Union was reluctant to release information about its design, and about the missions relating to the station.<ref name=Zimmerman>Robert Zimmerman (September 3, 2003). Leaving Earth: Space Stations, Rival Superpowers, and the Quest for Interplanetary Travel. Joseph Henry Press. pp. 544. ISBN 0-309-08548-9.</ref> It attained an altitude of 219 to 270&nbsp;km on launch<ref name=Bond>Peter Bond (20 June 2002). The continuing story of the International Space Station. Springer. p. 416. {{ISBN|1-85233-567-X}}.</ref> and NASA reported its final orbital altitude was 268 to 272&nbsp;km.<ref name=NASAcat>{{cite web|url=https://nssdc.gsfc.nasa.gov/nmc/spacecraft/display.action?id=1974-046A|title=Salyut 3 - NSSDC ID: 1974-046A|publisher=NASA}}</ref> The space stations funded and developed by the military, known as ''Almaz'' stations, were roughly similar in size and shape to the civilian DOS stations.<ref name=Zimmerman/> But the details of their design, which is attributed to Vladimir Chelomey, are considered to be significantly different from the DOS stations.<ref name=Zimmerman/> The first Almaz station was Salyut 2, which launched in April 1973, but failed only days after reaching orbit, and hence it was never manned.<ref name=Portree1995/> Salyut 3 consisted of an airlock chamber, a large-diameter work compartment, and a small diameter living compartment, giving a total habitable volume of 90 m³.<ref name=Portree/> It had two solar arrays, one docking port, and two main engines, each of which could produce 400 kgf (3.9 kN) of thrust.<ref name=Portree/> Its launch mass was 18,900 kg.<ref name=Portree1995/> The station came equipped with a shower, a standing sleeping station, as well as a foldaway bed.<ref name=Portree1995/> The floor was covered with hook and loop fastener (Velcro) to assist the cosmonauts moving around the station. Some entertainment on the station included a magnetic chess set, a small library, and a cassette deck with some audio compact Cassette tapes.<ref name=Portree/> Exercise equipment included a treadmill and Pingvin exercise suit.<ref name=Portree/> The first water-recycling facilities were tested on the station; the system was called Priboy.<ref name=Portree1995/> The work compartment was dominated by the ''Agat-1'' Earth-observation telescope, which had a focal length of 6.375 metres and an optical resolution better than three metres, according to post-Soviet sources;<ref name=Siddiqi/>. Another NASA source<ref name=Portree1995/> states the focal length was 10 metres; but Portree's document preceded Siddiqi's by several years, during which time more information about the specifications was gathered. NASA historian Siddiqi has speculated that given the size of the telescope's mirror, it likely had a resolution better than one metre.<ref name=Siddiqi>{{cite book|title=Challenge to Apollo: The Soviet Union and the Space Race, 1945-1974|author=Siddiqi, Asif A.|publisher=NASA|year=2000}} SP-2000-4408. [https://history.nasa.gov/SP-4408pt1.pdf Part 2 (page 1-499)], [https://history.nasa.gov/SP-4408pt2.pdf Part 1 (page 500-1011)]</ref> The telescope was used in conjunction with a wide-film camera, and was used primarily for military reconnaissance purposes.<ref name=Siddiqi/> The cosmonauts are said to have observed targets set out on the ground at Baikonur. Secondary objectives included study of water pollution, agricultural land, possible ore-bearing landforms, and oceanic ice formation.<ref name=Portree1995/> The Salyut 3, although called a "civilian" station, was equipped with a "self-defence" gun which had been designed for use aboard the station, and whose design is attributed to Alexander Nudelman.<ref name=Zak/> Some accounts claim the station was equipped with a Nudelman-Rikhter "Vulkan" gun, which was a variant of the Nudelman-Rikhter NR-23 (23 mm Nudelman) aircraft cannon, or possibly a Nudelman-Rikhter NR-30 (Nudelman NR-30) 30&nbsp;mm gun.<ref name=Olberg>[http://space.au.af.mil/books/oberg/ch02.pdf James Olberg, ''Space Power Theory'', Ch. 2]</ref> Later Russian sources indicate that the gun was the virtually unknown (in the West) Rikhter R-23.<ref>Широкоград А.Б. (2001) ''История авиационного вооружения'' Харвест (Shirokograd A.B. (2001) ''Istorya aviatsionnogo vooruzhenia'' Harvest. {{ISBN|985-433-695-6}}) (''History of aircraft armament'') p. 162</ref> These claims have reportedly been verified by Pavel Popovich, who had visited the station in orbit, as commander of Soyuz 14.<ref name=Olberg/> Due to potential shaking of the station, in-orbit tests of the weapon with cosmonauts in the station were ruled out.<ref name=Zak/> The gun was fixed to the station in such a way that the only way to aim would have been to change the orientation of the entire station.<ref name=Zak/><ref name=Olberg/> Following the last manned mission to the station, the gun was commanded by the ground to be fired; some sources say it was fired to depletion,<ref name=Olberg/> while other sources say three test firings took place during the Salyut 3 mission.<ref name=Zak/> {{clear}} ==Salyut 4== [[Image:Salyut-4 diagram.gif|thumb|right|250px|Diagram shows the orbital configuration of the Soviet space station Salyut 4 with a docked Soyuz 7K-T spacecraft. Credit: [[c:user:Bricktop|Bricktop]].{{tlx|free media}}]] Installed on the Salyut 4 were OST-1 (Orbiting Solar Telescope) 25&nbsp;cm solar telescope with a focal length of 2.5m and spectrograph shortwave diffraction spectrometer for far ultraviolet emissions, designed at the Crimean Astrophysical Observatory, and two X-ray telescopes.<ref>[http://www.friends-partners.org/partners/mwade/craft/salyut4.htm Salyut 4<!-- Bot generated title -->]</ref><ref>[http://adsabs.harvard.edu/abs/1979IzKry..59...31B The design of the Salyut-4 orbiting solar telescope]</ref> One of the X-ray telescopes, often called the ''Filin telescope'', consisted of four gas flow proportional counters, three of which had a total detection surface of 450&nbsp;cm² in the energy range 2–10 keV, and one of which had an effective surface of 37&nbsp;cm² for the range 0.2 to 2 keV (32 to 320 Attojoule (aJ)). The field of view was limited by a slit collimator to 3 in × 10 in full width at half maximum. The instrumentation also included optical sensors which were mounted on the outside of the station together with the X-ray detectors, and power supply and measurement units which were inside the station. Ground-based calibration of the detectors was considered along with in-flight operation in three modes: inertial orientation, orbital orientation, and survey. Data could be collected in 4 energy channels: 2 to 3.1 keV (320 to 497 aJ), 3.1 to 5.9 keV (497 to 945 aJ), 5.9 to 9.6 keV (945 to 1,538 aJ), and 2 to 9.6 keV (320 to 1,538 aJ) in the larger detectors. The smaller detector had discriminator levels set at 0.2 keV (32 aJ), 0.55 keV (88 aJ), and 0.95 keV (152 aJ).<ref name=Salyut4>{{cite web |title=Archived copy |accessdate=2012-05-05|url=https://web.archive.org/web/20120504183030/http://www.astronautix.com/craft/salyut4.htm }}</ref> Other instruments include a swivel chair for vestibular function tests, lower body negative pressure gear for cardiovascular studies, bicycle ergometer integrated physical trainer (electrically driven running track 1 m X .3 m with elastic cords providing 50&nbsp;kg load), penguin suits and alternate athletic suit, sensors for temperature and characteristics of upper atmosphere, ITS-K infrared telescope spectrometer and ultraviolet spectrometer for study of earth's infrared radiation, multispectral earth resources camera, cosmic ray detector, embryological studies, new engineering instruments tested for orientation of station by celestial objects and in darkness and a teletypewriter.<ref name=Salyut4/> {{clear}} ==Salyut 5== [[Image:Salyut 5.jpeg|thumb|right|250px|Image was obtained from the Almaz OPS page. Credit: [[c:user:Mpaoper|Mpaoper]].{{tlx|free media}}]] Salyut 5 carried Agat, a camera which the crews used to observe the Earth. The first manned mission, Soyuz 21, was launched from Baikonur on 6 July 1976, and docked at 13:40 UTC the next day.<ref name=Anikeev>{{cite web|last=Anikeev|first=Alexander|title=Soyuz-21|work=Manned Astronautics, Figures and Facts|accessdate=31 December 2010|url=https://web.archive.org/web/20110319191201/http://space.kursknet.ru/cosmos/english/machines/s21.sht }}</ref> On 14 October 1976, Soyuz 23 was launched carrying Vyacheslav Zudov and Valery Rozhdestvensky to the space station. During approach for docking the next day, a faulty sensor incorrectly detected an unexpected lateral motion. The spacecraft's Igla automated docking system fired the spacecraft's maneuvering thrusters in an attempt to stop the non-existent motion. Although the crew was able to deactivate the Igla system, the spacecraft had expended too much fuel to reattempt the docking under manual control. Soyuz 23 returned to Earth on 16 October without completing its mission objectives. The last mission to Salyut 5, Soyuz 24, was launched on 7 February 1977. Its crew consisted of cosmonauts Viktor Gorbatko and Yury Glazkov, who conducted repairs aboard the station and vented the air which had been reported to be contaminated. Scientific experiments were conducted, including observation of the sun. The Soyuz 24 crew departed on 25 February. The short mission was apparently related to Salyut 5 starting to run low on propellant for its main engines and attitude control system.<ref name=Zak/> {{clear}} ==Salyut 6== [[Image:Salyut 6.jpg|thumb|right|250px|Salyut 6 is photographed with docked Soyuz (right) and Progress (left). Credit: A cosmonaut of the Soviet space programme.{{tlx|fairuse}}]] Salyut 6 aka DOS-5, was a Soviet orbital space station, the eighth station of the Salyut programme. It was launched on 29 September 1977 by a Proton rocket. Salyut 6 was the first space station to receive large numbers of crewed and uncrewed spacecraft for human habitation, crew transfer, international participation and resupply, establishing precedents for station life and operations which were enhanced on Mir and the International Space Station. Salyut 6 was the first "second generation" space station, representing a major breakthrough in capabilities and operational success. In addition to a new propulsion system and its primary scientific instrument—the BST-1M multispectral telescope—the station had two docking ports, allowing two craft to visit simultaneously. This feature made it possible for humans to remain aboard for several months.<ref name=Chiara>{{cite book |title=Spacecraft: 100 Iconic Rockets, Shuttles, and Satellites that put us in Space |last1=De Chiara |first1=Giuseppe |last2=Gorn |first2=Michael H. |publisher=Quarto/Voyageur |date=2018 |location=Minneapolis |{{ISBN|9780760354186}} |pages=132–135}}</ref> Six long-term resident crews were supported by ten short-term visiting crews who typically arrived in newer Soyuz craft and departed in older craft, leaving the newer craft available to the resident crew as a return vehicle, thereby extending the resident crew's stay past the design life of the Soyuz. Short-term visiting crews routinely included international cosmonauts from Warsaw pact countries participating in the Soviet Union's Intercosmos programme. These cosmonauts were the first spacefarers from countries other than the Soviet Union or the United States. Salyut 6 was visited and resupplied by twelve uncrewed Progress spacecraft including Progress 1, the first instance of the series. Additionally, Salyut 6 was visited by the first instances of the new Soyuz-T spacecraft. {{clear}} ==Salyut 7== [[Image:Salyut7 with docked spacecraft.jpg|thumb|right|250px|A view of the Soviet orbital station Salyut 7, with a docked Soyuz spacecraft in view. Credit:NASA.{{tlx|fairuse}}]] Salyut 7 a.k.a. DOS-6, short for Durable Orbital Station<ref name=Portree1995/>) was a space station in low Earth orbit from April 1982 to February 1991.<ref name=Portree1995/> It was first crewed in May 1982 with two crew via Soyuz T-5, and last visited in June 1986, by Soyuz T-15.<ref name=Portree1995/> Various crew and modules were used over its lifetime, including 12 crewed and 15 uncrewed launches in total.<ref name=Portree1995/> Supporting spacecraft included the Soyuz T, Progress, and TKS spacecraft.<ref name=Portree1995/> {{clear}} ==Skylab== [[Image:Skylab (SL-4).jpg|thumb|right|250px|Skylab is an example of a manned observatory in orbit. Credit: NASA.{{tlx|free media}}]] Skylab included an Apollo Telescope Mount, which was a multi-spectral solar observatory. Numerous scientific experiments were conducted aboard Skylab during its operational life, and crews were able to confirm the existence of coronal holes in the Sun. The Earth Resources Experiment Package (EREP), was used to view the Earth with sensors that recorded data in the visible, infrared, and microwave spectral regions. {{clear}} ==Skylab 2== [[Image:40 Years Ago, Skylab Paved Way for International Space Station.jpg|thumb|right|250px|Skylab is photographed from the departing Skylab 2 spacecraft. Credit: NASA Skylab 2 crew.{{tlx|free media}}]] As the crew of Skylab 2 departs, the gold sun shield covers the main portion of the space station. The solar array at the top was the one freed during a spacewalk. The four, windmill-like solar arrays are attached to the Apollo Telescope Mount used for solar astronomy. {{clear}} ==Skylab 3== [[Image:Skylab 3 Close-Up - GPN-2000-001711.jpg|thumb|right|250px|Skylab is photographed by the arriving Skylab 3 crew. Credit: NASA Skylab 3 crew.{{tlx|free media}}]] A close-up view of the Skylab space station photographed against an Earth background from the Skylab 3 Command/Service Module during station-keeping maneuvers prior to docking. The Ilha Grande de Gurupá area of the Amazon River Valley of Brazil can be seen below. Aboard the command module were astronauts Alan L. Bean, Owen K. Garriott, and Jack R. Lousma, who remained with the Skylab space station in Earth's orbit for 59 days. This picture was taken with a hand-held 70mm Hasselblad camera using a 100mm lens and SO-368 medium speed Ektachrome film. Note the one solar array system wing on the Orbital Workshop (OWS) which was successfully deployed during extravehicular activity (EVA) on the first manned Skylab flight. The parasol solar shield which was deployed by the Skylab 2 crew can be seen through the support struts of the Apollo Telescope Mount. {{clear}} ==Skylab 4== [[Image:Skylab and Earth Limb - GPN-2000-001055.jpg|thumb|right|250px|The final view of Skylab, from the departing mission 4 crew, with Earth in the background. Credit: NASA Skylab 4 crew.{{tlx|free media}}]] An overhead view of the Skylab Orbital Workshop in Earth orbit as photographed from the Skylab 4 Command and Service Modules (CSM) during the final fly-around by the CSM before returning home. During launch on May 14, 1973, 63 seconds into flight, the micrometeor shield on the Orbital Workshop (OWS) experienced a failure that caused it to be caught up in the supersonic air flow during ascent. This ripped the shield from the OWS and damaged the tie-downs that secured one of the solar array systems. Complete loss of one of the solar arrays happened at 593 seconds when the exhaust plume from the S-II's separation rockets impacted the partially deployed solar array system. Without the micrometeoroid shield that was to protect against solar heating as well, temperatures inside the OWS rose to 126°F. The rectangular gold "parasol" over the main body of the station was designed to replace the missing micrometeoroid shield, to protect the workshop against solar heating. The replacement solar shield was deployed by the Skylab I crew. {{clear}} ==Spacelabs== [[Image:STS-42 view of payload bay.jpg|thumb|upright=1.0|right|300px|STS-42 is shown with Spacelab hardware in the orbiter bay overlooking Earth. Credit: NASA STS-42 crew.{{tlx|free media}}]] OSS-l (named for the NASA Office of Space Science and Applications) onboard STS-3 consisted of a number of instruments mounted on a Spacelab pallet, intended to obtain data on the near-Earth environment and the extent of contamination caused by the orbiter itself. Among other experiments, the OSS pallet contained a X-ray detector for measuring the polarization of X-rays emitted by solar flares.<ref name=Tramiel1984>{{cite journal|author=Tramiel, Leonard J.|author2=Chanan, Gary A. |author3=Novick, R.|title=Polarization evidence for the isotropy of electrons responsible for the production of 5-20 keV X-rays in solar flares|bibcode=1984ApJ...280..440T|date=1 May 1984|journal=The Astrophysical Journal|doi=10.1086/162010|volume=280|page=440}}</ref> Spacelab was a reusable laboratory developed by European Space Agency (ESA) and used on certain spaceflights flown by the Space Shuttle. The laboratory comprised multiple components, including a pressurized module, an unpressurized carrier, and other related hardware housed in the Shuttle's cargo bay. The components were arranged in various configurations to meet the needs of each spaceflight. "Spacelab is important to all of us for at least four good reasons. It expanded the Shuttle's ability to conduct science on-orbit manyfold. It provided a marvelous opportunity and example of a large international joint venture involving government, industry, and science with our European allies. The European effort provided the free world with a really versatile laboratory system several years before it would have been possible if the United States had had to fund it on its own. And finally, it provided Europe with the systems development and management experience they needed to move into the exclusive manned space flight arena."<ref>[https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19880009991.pdf ''Spacelab: An International Success Story'' Foreword by NASA Administrator James C. Fletcher]</ref> NASA shifted its focus from the Lunar missions to the Space Shuttle, and also space research.<ref name=Portree>{{cite web |url=https://spaceflighthistory.blogspot.com/2017/03/nasa-seeks-to-pep-up-shuttlespacelab.html |title=Spaceflight History: NASA Johnson's Plan to PEP Up Shuttle/Spacelab (1981) |last=Portree |first=David S.F. |date=2017 |website=Spaceflight History}}</ref> Spacelab consisted of a variety of interchangeable components, with the major one being a crewed laboratory that could be flown in Space Shuttle orbiter's bay and returned to Earth.<ref name="Angelo">{{cite book |author=Joseph Angelo |title=Dictionary of Space Technology |url=https://books.google.com/books?id=wSzfAQAAQBAJ&pg=PA393 |year=2013 |publisher=Routledge |{{isbn|978-1-135-94402-5}} |page=393}}</ref> However, the habitable module did not have to be flown to conduct a Spacelab-type mission and there was a variety of pallets and other hardware supporting space research.<ref name="Angelo"/> The habitable module expanded the volume for astronauts to work in a shirt-sleeve environment and had space for equipment racks and related support equipment.<ref name="Angelo"/> When the habitable module was not used, some of the support equipment for the pallets could instead be housed in the smaller Igloo, a pressurized cylinder connected to the Space Shuttle orbiter crew area.<ref name="Angelo"/> {| class="wikitable" |- ! Mission name ! Space Shuttle orbiter ! Launch date ! Spacelab <br>mission name ! Pressurized <br>module ! Unpressurized <br>modules |- | STS-2 | ''Columbia'' | November 12, 1981 | OSTA-1 | | 1 Pallet (E002)<ref name=STS2>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-2.html |title=STS-2 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-3 | ''Columbia'' | March 22, 1982 | OSS-1 | | 1 Pallet (E003)<ref name=STS3>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-3.html |title=STS-3 |publisher=NASA |accessdate=23 November 2010}}</ref> |- | STS-9 | ''Columbia'' | November 28, 1983 | Spacelab 1 | Module LM1 | 1 Pallet (F001) |- | STS-41-G | ''Challenger'' | October 5, 1984 | OSTA-3 | | 1 Pallet (F006)<ref name=NASA28>{{cite web |url=https://science.nasa.gov/science-news/science-at-nasa/1999/msad15mar99_1/ |title=Spacelab joined diverse scientists and disciplines on 28 Shuttle missions |publisher=NASA |date=15 March 1999 |accessdate=23 November 2010}}</ref> |- | STS-51-A | ''Discovery'' | November 8, 1984 | Retrieval of 2 satellites | | 2 Pallets (F007+F008) |- | STS-51-B | ''Challenger'' | April 29, 1985 | Spacelab 3 | Module LM1 | Multi-Purpose Experiment Support Structure (MPESS) |- | STS-51-F | ''Challenger'' | July 29, 1985 | Spacelab 2 | Igloo | 3 Pallets (F003+F004+F005) + IPS |- | STS-61-A | ''Challenger'' | October 30, 1985 | Spacelab D1 | Module LM2 | MPESS |- | STS-35 | ''Columbia'' | December 2, 1990 | ASTRO-1 | Igloo | 2 Pallets (F002+F010) + IPS |- | STS-40 | ''Columbia'' | June 5, 1991 | SLS-1 | Module LM1 | |- | STS-42 | ''Discovery'' | January 22, 1992 | IML-1 | Module LM2 | |- | STS-45 | ''Atlantis'' | March 24, 1992 | ATLAS-1 | Igloo | 2 Pallets (F004+F005) |- | STS-50 | ''Columbia'' | June 25, 1992 | USML-1 | Module LM1 | Extended Duration Orbiter (EDO) |- | STS-46 | ''Atlantis'' | July 31, 1992 | TSS-1 | | 1 Pallet (F003)<ref name=ESA-STS46>{{cite web |url=https://www.esa.int/Enabling_Support/Operations/ESA_hands_over_a_piece_of_space_history |title=ESA hands over a piece of space history |publisher=ESA}}</ref> |- | STS-47 (J) | ''Endeavour'' | September 12, 1992 | Spacelab-J | Module LM2 | |- | STS-56 | ''Discovery'' | April 8, 1993 | ATLAS-2 | Igloo | 1 Pallet (F008) |- | STS-55 (D2) | ''Columbia'' | April 26, 1993 | Spacelab D2 | Module LM1 | Unique Support Structure (USS) |- | STS-58 | ''Columbia'' | October 18, 1993 | SLS-2 | Module LM2 | EDO |- | STS-61 | ''Endeavour'' | December 2, 1993 | HST SM 01 | | 1 Pallet (F009) |- | STS-59 | ''Endeavour'' | April 9, 1994 | SRL-1 | | 1 Pallet (F006) |- | STS-65 | ''Columbia'' | July 8, 1994 | IML-2 | Module LM1 | EDO |- | STS-64 | ''Discovery'' | September 9, 1994 | LITE | | 1 Pallet (F007)<ref name=PraxisLog>{{cite book |title=Manned Spaceflight Log 1961–2006 |author=Tim Furniss |author2=David Shayler |author3=Michael Derek Shayler |publisher=Springer Praxis |page=829 |date=2007}}</ref> |- | STS-68 | ''Endeavour'' | September 30, 1994 | SRL-2 | | 1 Pallet (F006) |- | STS-66 | ''Atlantis'' | November 3, 1994 | ATLAS-3 | Igloo | 1 Pallet (F008) |- | STS-67 | ''Endeavour'' | March 2, 1995 | ASTRO-2 | Igloo | 2 Pallets (F002+F010) + IPS + EDO |- | STS-71 | ''Atlantis'' | June 27, 1995 | Spacelab-Mir | Module LM2 | |- | STS-73 | ''Columbia'' | October 20, 1995 | USML-2 | Module LM1 | EDO |- | STS-75 | ''Columbia'' | February 22, 1996 | TSS-1R / USMP-3 | | 1 Pallet (F003)<ref name=NASA28/> + 2 MPESS + EDO |- | STS-78 | ''Columbia'' | June 20, 1996 | LMS | Module LM2 | EDO |- | STS-82 | ''Discovery'' | February 21, 1997 | HST SM 02 | | 1 Pallet (F009)<ref name=NASA28/> |- | STS-83 | ''Columbia'' | April 4, 1997 | MSL-1 | Module LM1 | EDO |- | STS-94 | ''Columbia'' | July 1, 1997 | MSL-1R | Module LM1 | EDO |- | STS-90 | ''Columbia'' | April 17, 1998 | Neurolab | Module LM2 | EDO |- | STS-103 | ''Discovery'' | December 20, 1999 | HST SM 03A | | 1 Pallet (F009) |- | STS-99 | ''Endeavour'' | February 11, 2000 | SRTM | | 1 Pallet (F006) |- | STS-92 | ''Discovery'' | Oktober 11, 2000 | ISS assembly | | 1 Pallet (F005) |- | STS-100 | ''Endeavour'' | April 19, 2001 | ISS assembly | | 1 Pallet (F004) |- | STS-104 | ''Atlantis'' | July 12, 2001 | ISS assembly | | 2 Pallets (F002+F010) |- | STS-109 | ''Columbia'' | March 1, 2002 | HST SM 03B | | 1 Pallet (F009) |- | STS-123 | ''Endeavour'' | March 11, 2008 | ISS assembly | | 1 Pallet (F004) |- | STS-125 | ''Atlantis'' | May 11, 2009 | HST SM 04 | | 1 Pallet (F009) |} {{clear}} ==Spacelab 1== [[Image:Spacelab1 flight columbia.jpg|thumb|right|250px|Spacelab 1 was carried into space onboard STS-9. Credit: NASA STS-9 crew.{{tlx|free media}}]] The Spacelab 1 mission had experiments in the fields of space plasma physics, solar physics, atmospheric physics, astronomy, and Earth observation.<ref name=Shayler>{{cite book |url=https://books.google.com/books?id=TweEC3h633AC&pg=PA433 |title=NASA's Scientist-Astronauts |first1=David |last1=Shayler |last2=Burgess |first2=Colin |date=2007 |publisher=Springer Science & Business Media |{{isbn|978-0-387-49387-9}} |page=433 |bibcode=2006nasa.book.....S }}</ref> {{clear}} ==Spacelab 2== [[Image:STS-51-F Instrument Pointing System.jpg|thumb|right|250px|Spacelab 2 pallet is shown in the open payload bay of Space Shuttle ''Challenger''. Credit: NASA STS-19 crew.{{tlx|free media}}]] View of the Spacelab 2 pallet in the open payload bay. The solar telescope on the Instrument Pointing System (IPS) is fully deployed. The Solar UV high resolution Telescope and Spectrograph are also visible. The Spacelab Infrared Telescope (IRT) was also flown on the mission.<ref name=Kent/> The IRT was a {{cvt|15.2|cm}} aperture liquid helium-cooled infrared telescope, observing light between wavelengths of 1.7 to 118 μm.<ref name=Kent>[http://adsabs.harvard.edu/full/1992ApJS...78..403K Kent, et al. – '''Galactic structure from the Spacelab infrared telescope''' (1992)]</ref> It was thought heat emissions from the Shuttle corrupting long-wavelength data, but it still returned useful astronomical data.<ref name=Kent/> Another problem was that a piece of mylar insulation broke loose and floated in the line-of-sight of the telescope.<ref name=Kent/> IRT collected infrared data on 60% of the galactic plane.<ref name="ipac.caltech.edu">{{cite web |title=Archived copy of Infrared Astronomy From Earth Orbit|accessdate=2016-12-10|url=https://web.archive.org/web/20161221020839/http://www.ipac.caltech.edu/outreach/Edu/orbit.html }}</ref> A later space mission that experienced a stray light problem from debris was ''Gaia'' astrometry spacecraft launch in 2013 by the ESA - the source of the stray light was later identified as the fibers of the sunshield, protruding beyond the edges of the shield.<ref>{{cite news|url=http://www.cosmos.esa.int/web/gaia/news_20141217|title=STATUS OF THE GAIA STRAYLIGHT ANALYSIS AND MITIGATION ACTIONS|publisher=ESA|date=2014-12-17|accessdate=5 February 2022}}</ref> {{clear}} ==Spacelab 3== [[Image:Spacelab Module in Cargo Bay.jpg|thumb|right|250px|Spacelab Module is photographed in the Cargo Bay. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:Crystal in VCGS furnace.jpg|thumb|upright=1.0|left|250px|Mercuric iodide crystals were grown on STS-51-B, Spacelab 3. Credit: [[w:user:Lodewijk van den Berg|Lodewijk van den Berg]] and Marshall Space Flight Center, NASA.{{tlx|free media}}]] [[Image:Vapor Crystal Growth System Furnace.jpg|thumb|right|250px|The Vapor Crystal Growth System Furnace experiment is shown on STS-51-B. Credit: STS-17 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|left|250px|Space Shuttle ''Challenger'' launches on STS-51B. Credit: NASA.{{tlx|free media}}]] [[Image:STS51B-06-010.jpg|thumb|right|250px|Lodewijk van den Berg observes the crystal growth aboard Spacelab. Credit: NASA STS-17 crew.{{tlx|free media}}]] Van den Berg and his colleagues designed the EG&G Vapor Crystal Growth System experiment apparatus for a Space Shuttle flight. The experiment required an in-flight operator and NASA decided that it would be easier to train a crystal growth scientist to become an astronaut, than it would be the other way around. NASA asked EG&G and Van den Berg to compile a list of eight people who would qualify to perform the science experiments in space and to become a Payload Specialist. Van den Berg and his chief, Dr. Harold A. Lamonds could only come up with seven names. Lamonds subsequently proposed adding Van den Berg to the list, joking with Van den Berg that due to his age, huge glasses and little strength, he would probably be dropped during the first selection round; but at least they would have eight names. Van den Berg agreed to be added to the list, but didn't really consider himself being selected to be a realistic scenario.<ref name=Engelen>{{Cite news |title=Niet Wubbo maar Lodewijk van den Berg was de eerste |last=van Engelen |first=Gert |periodical=Delft Integraal |year=2005 |issue=3 |pages=23–26 |language=nl |accessdate=2017-08-24 |url=https://web.archive.org/web/20170824215339/http://actueel.tudelft.nl/fileadmin/UD/MenC/Support/Internet/TU_Website/TU_Delft_portal/Actueel/Magazines/Delft_Integraal/archief/2005_DI/2005-3/doc/DI05-3-5LodewijkvdBerg.pdf }}</ref><ref name="netwerk">{{cite video |title=De `vergeten astronaut` |url=https://web.archive.org/web/20091014203252/http://www.netwerk.tv/node/3884 |medium=documentary |publisher=Netwerk, NCRV and Evangelische Omroep (EO)|accessdate=2008-04-09 }}</ref> The first selection round consisted of a selection based on science qualifications in the field in question, which Van den Berg easily passed. The final four candidates were tested on physical and mental qualifications which he also passed, while two of the others failed due to possible heart issues. He was now part of the final two, and NASA always trains two astronauts, a prime and a back-up. In 1983 he started to train as an astronaut and six months before the launch he was told that he would be the prime astronaut, much to his own surprise. When he went into space he was 53 years old, making him one of the oldest rookie astronauts.<ref name=Engelen/><ref name="netwerk" /> {{clear}} ==Space Transportation Systems (STSs)== [[Image:Space Shuttle, Nuclear Shuttle, and Space Tug.jpg|thumb|right|250px|This artist's concept illustrates the use of the Space Shuttle, Nuclear Shuttle, and Space Tug in NASA's Integrated Program. Credit: NASA.{{tlx|free media}}]] The purpose of the system was two-fold: to reduce the cost of spaceflight by replacing the current method of launching capsules on expendable rockets with reusable spacecraft; and to support ambitious follow-on programs including permanent orbiting space stations around Earth and the Moon, and a human landing mission to Mars. The Space Shuttles were often used as short term orbital platforms. {{clear}} ==STS-1== [[Image:Space Shuttle Columbia launching.jpg|thumb|left|250px|The April 12, 1981, launch at Pad 39A of STS-1, just seconds past 7 a.m., carries astronauts John Young and Robert Crippen into an Earth orbital mission scheduled to last for 54 hours, ending with unpowered landing at Edwards Air Force Base in California. Credit: NASA.{{tlx|free media}}]] [[Image:Columbia STS-1 training.jpg|thumb|right|250px|STS-1 crew is shown in Space Shuttle Columbia's cabin. Credit: NASA.{{tlx|free media}}]] The majority of the ''Columbia'' crew's approximately 53 hours in low Earth orbit was spent conducting systems tests including Crew Optical Alignment Sight (COAS) calibration, star tracker performance, Inertial Measurement Unit (IMU) performance, manual and automatic Reaction Control System (RCS} testing, radiation measurement, propellant crossfeeding, hydraulics functioning, fuel cell purging and Earth photography. {{clear}} ==STS-2== [[Image:Aerial View of Columbia Launch - GPN-2000-001358.jpg|thumb|upright=1.0|left|250px|Aerial view shows ''Columbia'' launch from Pad 39A at the Kennedy Space Center in Florida. Credit: NASA / John Young aboard NASA's Shuttle Training Aircraft (STA).{{tlx|free media}}]] [[Image:STS-2 Canadarm debut.jpg|thumb|right|250px|On Space Shuttle mission STS-2, Nov. 1981, the Canadarm is flown in space for the first time. Credit: NASA.{{tlx|free media}}]] On a Spacelab pallet were a number of remote-sensing instruments including the Shuttle Imaging Radar-A (SIR-A), for remote sensing of Earth's resources, environmental quality, and ocean and weather conditions.<ref>{{cite web |url=https://web.archive.org/web/19970208115640/http://southport.jpl.nasa.gov/scienceapps/sira.html |title=SIR-A: 1982|publisher=NASA|accessdate= 22 June 2013}}</ref> The second launch of ''Columbia'' also included an onboard camera for Earth photography. {{clear}} ==STS-3== [[Image:STS-3 launch.jpg|thumb|upright=1.0|left|250px|STS-3 lifts off from Launch Complex-39A at Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:STS-3 infrared on reentry.jpg|thumb|upright=1.0|right|250px|The Kuiper Airborne Observatory took an infrared image of the orbiter's heat shield to study its operational temperatures. In this image, ''Columbia'' is travelling at Mach{{nbsp}}15.6 at an altitude of {{cvt|56|km}}. Credit: .{{tlx|free media}}]] in its payload bay, ''Columbia'' again carried the Development Flight Instrumentation (DFI) package, and a test canister for the Small Self-Contained Payload program – also known as the Getaway Special (GAS) – was mounted on one side of the payload bay. {{clear}} ==STS-4== [[Image:STS-4 launch.jpg|thumb|left|250px|Launch view of the Space Shuttle ''Columbia'' for the STS-4 mission. Credit: NASA.{{tlx|free media}}]] [[Image:STS-4 Induced Environment Contaminant Monitor.jpg|thumb|right|250px|View shows the Space Shuttle's RMS grappling the Induced Environment Contaminant Monitor (IECM) experiment. Credit: NASA STS-4 crew.{{tlx|free media}}]] The North Atlantic Ocean southeast of the Bahamas is in the background as Columbia's remote manipulator system (RMS) arm and end effector grasp a multi-instrument monitor for detecting contaminants. The experiment is called the induced environment contaminant monitor (IECM). Below the IECM the tail of the orbiter can be seen. In the shuttle's mid-deck, a Continuous Flow Electrophoresis System and the Mono-disperse Latex Reactor flew for the second time. The crew conducted a lightning survey with hand-held cameras, and performed medical experiments on themselves for two student projects. They also operated the Remote Manipulator System (Canadarm) with an instrument called the Induced Environment Contamination Monitor mounted on its end, designed to obtain information on gases or particles being released by the orbiter in flight.<ref name=JSC>{{cite web|url=http://www.jsc.nasa.gov/history/shuttle_pk/pk/Flight_004_STS-004_Press_Kit.pdf|title=STS-004 Press Kit|publisher=NASA|accessdate=4 July 2013}}</ref> {{clear}} ==STS-7== [[Image:Challenger launch on STS-7.jpg|thumb|left|250px|Space Shuttle Challenger launches on STS-7. Credit: NASA.{{tlx|free media}}]] [[Image:Space debris impact on Space Shuttle window.jpg|thumb|right|250px|An impact crater is in one of the windows of the Space Shuttle ''Challenger'' following a collision with a paint chip during STS-7. Credit: NASA STS-7 crew.{{tlx|free media}}]] STS-7 was NASA's seventh Space Shuttle mission, and the second mission for the Space Shuttle ''Challenger''. Norman Thagard, a mission specialist, conducted medical tests concerning Space adaptation syndrome, a bout of nausea frequently experienced by astronauts during the early phase of a space flight. The mission carried the first Shuttle pallet satellite (SPAS-1), built by Messerschmitt-Bölkow-Blohm (MBB). SPAS-1 was unique in that it was designed to operate in the payload bay or be deployed by the Remote Manipulator System (Canadarm) as a free-flying satellite. It carried 10 experiments to study formation of metal alloys in microgravity, the operation of heat pipes, instruments for remote sensing observations, and a mass spectrometer to identify various gases in the payload bay. It was deployed by the Canadarm and flew alongside and over ''Challenger'' for several hours, performing various maneuvers, while a U.S.-supplied camera mounted on SPAS-1 took pictures of the orbiter. The Canadarm later grappled the pallet and returned it to the payload bay. STS-7 also carried seven Getaway Special (GAS) canisters, which contained a wide variety of experiments, as well as the OSTA-2 payload, a joint U.S.-West Germany scientific pallet payload. The orbiter's Ku-band antenna was able to relay data through the U.S. tracking and data relay satellite (TDRS) to a ground terminal for the first time. {{clear}} ==STS-8== [[Image:STS_8_Launch.jpg|thumb|left|250|Space Shuttle ''Challenger'' begins its third mission on 30 August 1983, conducting the first night launch of the shuttle program. Credit: NASA.{{tlx|free media}}]] STS-8 was the eighth NASA Space Shuttle mission and the third flight of the Space Shuttle ''Challenger''. The secondary payload, replacing a delayed NASA communications satellite, was a four-metric-ton dummy payload, intended to test the use of the shuttle's Canadarm (remote manipulator system). Scientific experiments carried on board ''Challenger'' included the environmental testing of new hardware and materials designed for future spacecraft, the study of biological materials in electric fields under microgravity, and research into space adaptation syndrome (also known as "space sickness"). The Payload Flight Test Article (PFTA) had been scheduled for launch in June 1984 on STS-16 in the April 1982 manifest,<ref name="news 82-46">{{cite press release|url=https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/19820014425.pdf|hdl=2060/19820014425|title=Space Shuttle payload flight manifest / News Release 82-46|date=April 14, 1982|publisher=NASA |last1=McCormack |first1= Dick |last2=Hess |first2=Mark |archive-url=https://web.archive.org/web/20220412163838/https://ntrs.nasa.gov/citations/19820014425 |archive-date=2022-04-12 |url-status=live }}</ref> but by May 1983 it had been brought forward to STS-11. That month, when the TDRS missions were delayed, it was brought forward to STS-8 to fill the hole in the manifest.<ref name="STS-8 Press Information, p. i">''STS-8 Press Information'', p. i</ref> It was an aluminum structure resembling two wheels with a {{cvt|6|m}} long central axle, ballasted with lead to give it a total mass of {{cvt|3855|kg}}, which could be lifted by the Canadarm Remote Manipulator System – the Shuttle's "robot arm" – and moved around to help astronauts gain experience in using the system. It was stored in the midsection of the payload bay.<ref>Press kit, p. 32</ref> The orbiter carried the Development Flight Instrumentation (DFI) pallet in its forward payload bay; this had previously flown on ''Columbia'' to carry test equipment. The pallet was not outfitted with any flight instrumentation, but was used to mount two experiments. The first studied the interaction of ambient atomic oxygen with the structural materials of the orbiter and payload, while the second tested the performance of a heat pipe designed for use in the heat rejection systems of future spacecraft.<ref>Press kit, pp. 38–39. The first experiment was formally designated "Evaluation of Oxygen Interaction with Materials" (DSO-0301) while the second was the High Capacity Heat Pipe Demonstration (DSO-0101)</ref> Four Getaway Special (GAS) payloads were carried. One studied the effects of cosmic rays on electronic equipment. The second studied the effect of the gas environment around the orbiter using ultraviolet absorption measurements, as a precursor to ultraviolet equipment being designed for Spacelab 2. A third, sponsored by the Japanese ''Asahi Shimbun'' newspaper, tried to use water vapor in two tanks to create snow crystals. This was a second attempt at an experiment first flown on STS-6, which had had to be redesigned after the water in the tanks froze solid. The last was similar to an experiment flown on STS-3, and studied the ambient levels of atomic oxygen by measuring the rates at which small carbon and osmium wafers oxidized.<ref>Press kit, pp. 40–41. In order, these were designated the Cosmic Ray Upset Experiment (CRUX) (G-0346); the Ultraviolet-Sensitive Photographic Emulsion Experiment (G-0347); the Japanese snow crystal experiment (G-0475), and the Contamination Monitor Package (G-0348).</ref> The mission, in cooperation with the United States Postal Service (USPS), also carried 260,000 postal covers franked with US$9.35 express postage stamps, which were to be sold to collectors, with the profits divided between the USPS and NASA. Two storage boxes were attached to the DFI pallet, with more stored in six of the Getaway Special canisters.<ref>Press kit, p. 37</ref> A number of other experiments were to be performed inside the orbiter crew compartment. Among these was the Continuous Flow Electrophoresis System, being flown for the fourth time. This separated solutions of biological materials by passing electric fields through them; the experiment aimed at supporting research into diabetes treatments.<ref>Press kit, p. 38</ref> A small animal cage was flown containing six rats; no animal experiment was carried out on the flight, but a student involvement project was planned for a later mission which would use the cage, and NASA wanted to ensure it was flight-tested.<ref name="Press kit, p. 39">Press kit, p. 39</ref> The student involvement project carried out on STS-8 involved William E. Thornton using biofeedback techniques, to try to determine if they worked in microgravity.<ref name="Press kit, p. 39"/> A photography experiment would attempt to study the spectrum of a luminous atmospheric glow which had been reported around the orbiter, and determine how this interacted with firings of the reaction control system (RCS).<ref>''STS-9 Press Information'', p. 60. This was formally designated as "Investigation of STS Atmospheric Luminosities".</ref> {{clear}} ==STS-9== [[Image:Sts-9lift.jpg|thumb|left|250px|Columbia launches on mission STS-9 from Launch Pad 39-A. Credit: NASA.{{tlx|free media}}]] STS-9 (also referred to Spacelab 1) <ref>"Fun facts about STS numbering"|url=https://web.archive.org/web/20100527232806/http://enterfiringroom.ksc.nasa.gov/funFactsSTSNumbers.htm|date=2010-05-27 |NASA/KSC 29 October 2004. Retrieved 20 July 2013</ref> was the ninth NASA Space Shuttle mission and the sixth mission of the Space Shuttle ''Columbia''. Launched on 28 November 1983, the ten-day mission carried the first Spacelab laboratory module into orbit. The mission was devoted entirely to Spacelab 1, a joint NASA/European Space Agency (ESA) program designed to demonstrate the ability to conduct advanced scientific research in space. Both the mission specialists and payload specialists worked in the Spacelab module and coordinated their efforts with scientists at the Marshall Space Flight Center (MSFC) Payload Operations Control Center (POCC), which was then located at the Johnson Space Center (JSC) in Texas. Funding for Spacelab 1 was provided by the ESA. Over the course of the mission, 72 scientific experiments were carried out, spanning the fields of atmospheric and plasma physics, astronomy, solar physics, material sciences, technology, astrobiology and Earth observations. The Spacelab effort went so well that the mission was extended an additional day to 10 days, making it the longest-duration shuttle flight at that time. {{clear}} ==STS-13== [[Image:SMMS repair by STS-41C Astronauts.jpg|thumb|right|250px|Mission Specialists George Nelson and James D. A. van Hoften repair the captured Solar Maximum Mission satellite on 11 April 1984. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] [[Image:EL-1994-00475.jpeg|thumb|left|250px|The launch of STS-41-C on 6 April 1984 is shown. Credit: NASA.{{tlx|free media}}]] [[Image:STS-41-C-LDEF-deploy-small.jpg|thumb|left|250px|The deployed Long Duration Exposure Facility (LDEF) became an important source of information on the small-particle space debris environment. Credit: NASA STS-13 (STS-41-C) crew.{{tlx|free media}}]] STS-41-C (formerly STS-13) was NASA's eleventh Space Shuttle mission, and the fifth mission of Space Shuttle ''Challenger''.<ref name=Hoften>[http://www.jsc.nasa.gov/history/oral_histories/vanHoftenJD/vanHoftenJDA_12-5-07.pdf James D. A. van Hoften] NASA Johnson Space Center Oral History Project. 5 December 2007 Retrieved 20 July 2013</ref><ref name=Hart>[http://www.jsc.nasa.gov/history/oral_histories/HartTJ/HartTJ_4-10-03.pdf Terry J. Hart] NASA Johnson Space Center Oral History Project. April 10, 2003 Retrieved July 20, 2013</ref> On the second day of the flight, the LDEF was grappled by the Remote Manipulator System (Canadarm) and successfully released into orbit. Its 57 experiments, mounted in 86 removable trays, were contributed by 200 researchers from eight countries. Retrieval of the passive LDEF was initially scheduled for 1985, but schedule delays and the ''Challenger'' disaster of 1986 postponed the retrieval until 12 January 1990, when ''Columbia'' retrieved the LDEF during STS-32. {{clear}} ==STS-14== [[Image:STS-41-D launch August 30, 1984.jpg|thumb|left|250px|The launch of Space Shuttle ''Discovery'' on its first mission on 30 August 1984. Credit: NASA.{{tlx|free media}}]] [[Image:STS41D-01-021.jpg|thumb|right|250px|View of the OAST-1 solar array on STS-41-D is shown. Credit: NASA STS-14 crew.{{tlx|free media}}]] STS-41-D (formerly STS-14) was the 12th flight of NASA's Space Shuttle program, and the first mission of Space Shuttle ''Discovery''. A number of scientific experiments were conducted, including a prototype electrical system of the International Space Station, or extendable solar array, that would eventually form the basis of the main solar arrays on the International Space Station (ISS). The OAST-1 photovoltaic module (solar array), a device {{cvt|4|m}} wide and {{cvt|31|m}} high, folded into a package {{cvt|18|cm}} deep. The array carried a number of different types of experimental solar cells and was extended to its full height several times during the mission. At the time, it was the largest structure ever extended from a crewed spacecraft, and it demonstrated the feasibility of large lightweight solar arrays for use on future orbital installations, such as the International Space Station (ISS). A student experiment to study crystal growth in microgravity was also carried out. {{clear}} ==STS-17== [[Image:SIR-B Sudbury Impact Crater.jpg|thumb|upright=1.0|right|250px|Sample image was taken using the SIR-B over Canada. Credit: NASA STS-17 crew.{{tlx|free media}}]] [[Image:STS-41-G SIR-B antenna.jpg|thumb|upright=1.0|left|250px|SIR-B antenna deployment is shown. Credit: NASA STS-17 crew.{{tlx|free media}}]] STS-41-G (formerly STS-17) was the 13th flight of NASA's Space Shuttle program and the sixth flight of Space Shuttle ''Challenger''. ''Challenger'' launched on 5 October 1984. The Shuttle Imaging Radar-B (SIR-B) was part of the OSTA-3 experiment package (Spacelab) in the payload bay, which also included the Large Format Camera (LFC) to photograph the Earth, another camera called MAPS which measured air pollution, and a feature identification and location experiment called FILE, which consisted of two TV cameras and two {{cvt|70|mm}} still cameras. The SIR-B was an improved version of a similar device flown on the OSTA-1 package during STS-2. It had an eight-panel antenna array measuring {{cvt|11|xx|2|m}}. It operated throughout the flight, but much of the data had to be recorded on board the orbiter rather than transmitted to Earth in real-time as was originally planned. SIR-B radar image of the Sudbury impact structure (elliptical because of deformation by Grenville thrusting) and the nearby Wanapitei crater (lake-filled) formed much later. The partially circular lake-filled structure on the right (east) is the 8 km (5 mi) wide Wanapitei crater, estimated to have formed 34 million years (m.y.) ago. The far larger Sudbury structure (second largest on Earth) appears as a pronounced elliptical pattern, more strongly expressed by the low hills to the north. This huge impact crater, with its distinctive outline, was created about 1800 m.y. ago. Some scientists argue that it was at least 245 km (152 mi) across when it was circular. More than 900 m.y. later strong northwestward thrusting of the Grenville Province terrane against the Superior Province (containing Sudbury) subsequently deformed it into its present elliptical shape (geologists will recognize this as a prime example of the "strain ellipsoid" model). After Sudbury was initially excavated, magmas from deep in the crust invaded the breccia filling, mixing with it and forming a boundary layer against its walls. Some investigators think that the resulting norite rocks are actually melted target rocks. This igneous rock (called an "irruptive") is host to vast deposits of nickel and copper, making this impact structure a 5 billion dollar source of ore minerals since mining began in the last century. Payload Specialist Scully-Power, an employee of the U.S. Naval Research Laboratory (NRL), performed a series of oceanography observations during the mission. Garneau conducted a series of experiments sponsored by the Canadian government, called CANEX, which were related to medical, atmospheric, climatic, materials and robotic science. A number of Getaway Special (GAS) canisters, covering a wide variety of materials testing and physics experiments, were also flown. {{clear}} ==STS-19== STS-51-A (formerly STS-19) was the 14th flight of NASA's Space Shuttle program, and the second flight of Space Shuttle ''Discovery''. The mission launched from Kennedy Space Center on 8 November 1984, and landed just under eight days later on 16 November 1984. STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. It launched from Kennedy Space Center, Florida, on 29 July 1985, and landed just under eight days later on 6 August 1985. Names: Space Transportation System-19 and Spacelab 2. ==STS-21== STS-51-D was the 16th flight of NASA's Space Shuttle program, and the fourth flight of Space Shuttle ''Discovery''.<ref name=PressKitit51D>{{cite web |url=http://www.shuttlepresskit.com/STS-51D/STS51D.pdf|title=STS-51D Press Kit|author=NASA|accessdate=December 16, 2009}}</ref> ''Discovery''s other mission payloads included the Continuous Flow Electrophoresis System III (CFES-III), which was flying for sixth time; two Shuttle Student Involvement Program (SSIP) experiments; the American Flight Echo-cardiograph (AFE); two Getaway specials (GASs); a set of Phase Partitioning Experiments (PPE); an astronomical photography verification test; various medical experiments; and "Toys in Space", an informal study of the behavior of simple toys in a microgravity environment, with the results being made available to school students upon the shuttle's return.<ref>{{cite web |url=https://www.nasa.gov/mission_pages/shuttle/shuttlemissions/archives/sts-51D.html|title=STS-51D|publisher=NASA|accessdate=January 16, 2018|date=February 18, 2010}}</ref> ==STS-22== [[Image:STS-51-B crew in Spacelab.jpg|thumb|right|250px|Space Transportation System-17, Spacelab 3, Overmyer, Lind, van den Berg, and Thornton are in the Spacelab Module LM1 during flight. Credit: STS-22 crew.{{tlx|free media}}]] [[Image:STS-51B launch.jpg|thumb|upright=1.0|left|250px|Launch of STS-51B is shown. Credit:NASA.{{tlx|free media}}]] STS-51B was the 17th flight of NASA's Space Shuttle program, and the seventh flight of Space Shuttle ''Challenger''. STS-51B was the second flight of the European Space Agency (ESA)'s Spacelab pressurized module, and the first with the Spacelab module in a fully operational configuration. Spacelab's capabilities for multi-disciplinary research in microgravity were successfully demonstrated. The gravity gradient attitude of the orbiter proved quite stable, allowing the delicate experiments in materials processing and fluid mechanics to proceed normally. The crew operated around the clock in two 12-hour shifts. Two squirrel monkeys and 24 Brown rats were flown in special cages,<ref>|url=https://web.archive.org/web/20110719061203/http://lis.arc.nasa.gov/lis/Programs/STS/STS_51B/STS_51B.html|date=July 19, 2011</ref> the second time American astronauts flew live non-human mammals aboard the shuttle. The crew members in orbit were supported 24 hours a day by a temporary Payload Operations Control Center, located at the Johnson Space Center. On the mission, Spacelab carried 15 primary experiments, of which 14 were successfully performed. Two Getaway Special (GAS) experiments required that they be deployed from their canisters, a first for the program. These were NUSAT (Northern Utah Satellite) and GLOMR (Global Low Orbiting Message Relay satellite). NUSAT deployed successfully, but GLOMR did not deploy, and was returned to Earth. {{clear}} ==STS-23== [[Image:STS-51-G Morelos 1 deployment.jpg|thumb|right|250px|Mexico's Morelos satellite deploys from Discovery's payload bay. Credit: NASA STS-23 crew.{{tlx|free media}}]] [[Image:STS-51-G Spartan 1.jpg|thumb|left|250px|Spartan 1 is shown after deployment on STS-51-G. Credit: NASA STS-23 crew.{{tlx|free media}}]] STS-51-G was the 18th flight of NASA's Space Shuttle program, and the fifth flight of Space Shuttle ''Discovery''. The SPARTAN-1 (Shuttle Pointed Autonomous Research Tool for AstroNomy) a deployable/retrievable carrier module, was designed to be deployed from the orbiter and fly free in space before being retrieved. SPARTAN-1 included {{cvt|140|kg}} of astronomy experiments. It was deployed and operated successfully, independent of the orbiter, before being retrieved. ''Discovery'' furthermore carried an experimental materials-processing furnace, two French biomedical experiments (French Echocardiograph Experiment (FEE) and French Postural Experiment (FPE)),<ref name=SF51G>{{cite web|title=STS-51G|url=http://spacefacts.de/mission/english/sts-51g.htm|publisher=Spacefacts|accessdate=23 January 2021}}</ref> and six Getaway Special (GAS) experiments, which were all successfully performed, although the GO34 Getaway Special shut down prematurely. This mission was also the first flight test of the OEX advanced autopilot which gave the orbiter capabilities above and beyond those of the baseline system. The mission's final payload element was a High Precision Tracking Experiment (HPTE) for the Strategic Defense Initiative (SDI) (nicknamed "Star Wars"); the HPTE successfully deployed on orbit 64. {{clear}} ==STS-24== [[Image:STS-51-F shuttle.jpg|thumb|upright=1.0|left|250px|Aborted launch attempt is at T-3 seconds on 12 July 1985. Credit: NASA.{{tlx|free media}}]] [[Image:STS-51-F Plasma Diagnostics Package.jpg|thumb|upright=1.0|right|250px|The Plasma Diagnostics Package (PDP) is grappled by the Canadarm. Credit: NASA STS-24 crew.{{tlx|free media}}]] [[Image:Isabella lake STS51F-42-34.jpg|thumb|upright=1.0|right|250px|A view of the Sierra Nevada mountains and surroundings from Earth orbit was taken on the STS-51-F mission. Credit: NASA STS-24 crew.{{tlx|free media}}]] STS-51-F (also known as Spacelab 2) was the 19th flight of NASA's Space Shuttle program and the eighth flight of Space Shuttle ''Challenger''. STS-51-F's primary payload was the laboratory module Spacelab 2. A special part of the modular Spacelab system, the "Spacelab igloo", which was located at the head of a three-pallet train, provided on-site support to instruments mounted on pallets. The main mission objective was to verify performance of Spacelab systems, determine the interface capability of the orbiter, and measure the environment created by the spacecraft. Experiments covered life sciences, plasma physics, astronomy, high-energy astrophysics, solar physics, atmospheric physics and technology research. Despite mission replanning necessitated by ''Challenger''s abort to orbit trajectory, the Spacelab mission was declared a success. The flight marked the first time the European Space Agency (ESA) Instrument Pointing System (IPS) was tested in orbit. This unique pointing instrument was designed with an accuracy of one arcsecond. Initially, some problems were experienced when it was commanded to track the Sun, but a series of software fixes were made and the problem was corrected. In addition, Anthony W. England became the second amateur radio operator to transmit from space during the mission. The Plasma Diagnostics Package (PDP), which had been previously flown on STS-3, made its return on the mission, and was part of a set of plasma physics experiments designed to study the Earth's ionosphere. During the third day of the mission, it was grappled out of the payload bay by the Remote Manipulator System (Canadarm) and released for six hours.<ref name=report>{{cite web|title=STS-51F National Space Transportation System Mission Report|url=https://www.scribd.com/doc/52621059/STS-51F-National-Space-Transportation-System-Mission-Report|publisher=NASA Lyndon B. Johnson Space Center|accessdate=March 1, 2014|page=2|date=September 1985}}</ref> During this time, ''Challenger'' maneuvered around the PDP as part of a targeted proximity operations exercise. The PDP was successfully grappled by the Canadarm and returned to the payload bay at the beginning of the fourth day of the mission.<ref name=report/> In an experiment during the mission, thruster rockets were fired at a point over Tasmania and also above Boston to create two "holes" – plasma depletion regions – in the ionosphere. A worldwide group collaborated with the observations made from Spacelab 2.<ref>{{cite web|url=http://harveycohen.net/essex/index.htm|title=Elizabeth A. Essex-Cohen Ionospheric Physics Papers |date=2007|accessdate=5 February 2022}}</ref> {{clear}} ==STS-43== [[Image:STS-43 Launch - GPN-2000-000731.jpg|thumb|upright=1.0|left|250px|Launch shows Space Shuttle ''Atlantis'' from the Kennedy Space Center. Credit: NASA.{{tlx|free media}}]] [[Image:Sts-43crew.jpg|thumb|upright=1.0|right|250px|Crew members pose for on-orbit portrait in the middeck of ''Atlantis''. Credit: NASA STS-43 crew.{{tlx|free media}}]] STS-43, the ninth mission for Space Shuttle ''Atlantis'', was a nine-day mission to test an advanced heatpipe radiator for potential use on the then-future space station, conduct a variety of medical and materials science investigations, and conduct astronaut photography of Earth. On the left, the Space Shuttle ''Atlantis'' streaks skyward as sunlight pierces through the gap between the orbiter and ET assembly. ''Atlantis'' lifted off on the 42nd space shuttle flight at 11:02 a.m. EDT on August 2, 1991 carrying a crew of five and TDRS-E. A remote camera at the 275-foot level of the Fixed Surface Structure took this picture. STS-43 crewmembers pose for on-orbit (in space) portrait on the middeck of ''Atlantis'', Orbiter Vehicle (OV) 104. At the left side of the frame are the forward lockers and at the right is the open airlock hatch. In between and in front of the starboard wall-mounted sleep restraints are (left to right) Mission Specialist (MS) G. David Low, MS Shannon W. Lucid, MS James C. Adamson, Commander John E. Blaha, and Pilot Michael A. Baker. {{clear}} ==Reflections== {{main|Radiation astronomy/Reflections}} [[Image:Ash and Steam Plume, Soufriere Hills Volcano, Montserrat.jpg|thumb|right|250px|This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-grey volcanic ash and steam plume extending westwards from the Soufriere Hills volcano. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Soufrière Hills, a volcano on the island of Montserrat, in the Lesser Antilles island chain in the Caribbean Sea, has been active since 1995. The most recent eruptive phase of the volcano began with a short swarm of volcano-tectonic earthquakes—earthquakes thought to be caused by movement of magma beneath a volcano—on October 4, 2009, followed by a series of ash-venting events that have continued through October 13, 2009. These venting events create plumes that can deposit ash at significant distances from the volcano. In addition to ash plumes, pyroclastic flows and lava dome growth have been reported as part of the current eruptive activity. This oblique astronaut photograph from the International Space Station (ISS) captures a white-to-gray ash and steam plume extending westwards from the volcano on October 11, 2009. Oblique images are taken by astronauts looking out from the ISS at an angle, rather than looking straight downward toward the Earth (a perspective called a nadir view), as is common with most remotely sensed data from satellites. An oblique view gives the scene a more three-dimension quality, and provides a look at the vertical structure of the volcanic plume. While much of the island is covered in green vegetation, gray deposits that include pyroclastic flows and volcanic mudflows (lahars) are visible extending from the volcano toward the coastline. When compared to its extent in earlier views, the volcanic debris has filled in more of the eastern coastline. Urban areas are visible in the northern and western portions of the island; they are recognizable by linear street patterns and the presence of bright building rooftops. The silver-gray appearance of the Caribbean Sea surface is due to sunglint, which is the mirror-like reflection of sunlight off the water surface back towards the handheld camera onboard the ISS. The sunglint highlights surface wave patterns around the island. {{clear}} ==Visuals== {{main|Radiation astronomy/Visuals}} [[Image:El Misti Volcano and Arequipa, Peru.jpg|thumb|right|250px|This mosaic of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. Credit: This image was taken by the NASA Expedition 21 crew.{{tlx|free media}}]] This mosaic on the right of two astronaut photographs illustrates the closeness of Arequipa, Peru, to the 5,822-meter-high El Misti Volcano. The city centre of Arequipa, Peru, lies only 17 kilometres away from the summit of El Misti; the grey urban area is bordered by green agricultural fields (image left). Much of the building stone for Arequipa, known locally as sillar, is quarried from nearby pyroclastic flow deposits that are white. Arequipa is known as “the White City” because of the prevalence of this building material. The Chili River extends north-eastwards from the city centre and flows through a canyon (image right) between El Misti volcano and Nevado Chachani to the north. {{clear}} ==Blues== {{main|Radiation astronomy/Blues}} [[Image:Ifalik ISS021.png|thumb|right|250px|NASA astronaut image is of Ifalik Atoll, Yap State, Federated States of Micronesia. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] Ifalik is a coral atoll of four islands in the central Caroline Islands in the Pacific Ocean, and forms a legislative district in Yap State in the Federated States of Micronesia. Ifalik is located approximately {{convert|40|km|mi}} east of Woleai and {{convert|700|km|mi}} southeast of the island of Yap. The population of Ifalik was 561 in 2000,<ref>{{cite web|website=The Pacific Community|url=https://web.archive.org/web/20100924233537/http://www.spc.int/prism/country/fm/stats/Census%20%26%20Surveys/2000/Yap-BT.pdf |title=Census & Surveys: 2000: Yap|accessdate=4 September 2020}}</ref> living on 1.5&nbsp;km². The primary islets of Ifalik are called Ella, Elangelap, Rawaii, and Falalop, which is the atoll's main island.<ref>[http://www.pacificweb.org/DOCS/fsm/Yap2000Census/2000%20Yap%20Census%20Report_Final.pdf Pacificweb]</ref> The total land area of Ifalik is only {{convert|1.47 |km2|sqmi}}, but it encloses a {{convert|20|m|ft}} deep lagoon of {{convert|2.43|km2|sqmi}}.<ref>Otis W. Freeman, ed., Geography of the Pacific, Wiley 1953</ref> The total area is about six square kilometers.<ref>[ftp://rock.geosociety.org/pub/reposit/2001/2001075.pdf Geosociety], January 2020, InternetArchiveBot</ref> Ifalik is known as a “warrior island”. Prior to European contact, its warriors invaded the outer islands in Yap as well as some of the outer islands in Chuuk. Atolls under the attack included, Lamotrek, Faraulep, Woleai, Elato, Satawal, Ulithi, and Poluwat (outer islet of Chuuk). {{clear}} ==Greens== {{main|Radiation astronomy/Greens}} [[Image:ISS021-E-15710 Pearl Harbor, Hawaii.jpg|thumb|right|250px|This detailed astronaut photograph illustrates the southern coastline of the Hawaiian island Oahu, including Pearl Harbor. Credit: ISS Expedition 21 Crew Earth Observations.{{tlx|free media}}]] A comparison between this image and a 2003 astronaut photograph of Pearl Harbor suggests that little observable land use or land cover change has occurred in the area over the past six years. The most significant difference is the presence of more naval vessels in the Reserve Fleet anchorage in Middle Loch (image center). The urban areas of Waipahu, Pearl City, and Aliamanu border the harbor to the northwest, north, and east. The built-up areas, recognizable by linear streets and white rooftops, contrast sharply with the reddish volcanic soils and green vegetation on the surrounding hills. {{clear}} ==Oranges== {{main|Radiation astronomy/Oranges}} [[Image:Northern Savage Island, Atlantic Ocean.jpg|thumb|right|250px|Selvagem Grande, with an approximate area of 4 square kilometres, is the largest of the Savage Islands. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Ounianga Lakes from ISS.jpg|thumb|left|250px|This astronaut photograph features one of the largest of a series of ten mostly fresh water lakes in the Ounianga Basin in the heart of the Sahara Desert of northeastern Chad. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] [[Image:Southern Savage Islands, Atlantic Ocean.jpg|thumb|right|250px|The irregularly-shaped Ilhéus do Norte, Ilhéu de Fora, and Selvagem Pequena are visible in the centre of the image. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] Selvagem Grande Island is part of the Savage Islands archipelago, which themselves are part of the Portuguese Autonomous Region of Madeira in the North Atlantic Ocean. The island ({{convert|2000|x|1700|m}}) belongs to the northeast group of the Savage Islands, which comprises in addition three islets: Sinho Islet, Palheiro de Terra and Palheiro do Mar.<ref name="NatGeoReport" /> It is generally flat, but has three summits, remnants of former volcanic cones appropriately named Atalaia, Tornozelos and Inferno, Atalaia being the highest of the three, reaching {{convert|163|m|ft|0|abbr=on}} in altitude.<ref name="NatGeoReport">{{cite web |title=Marine Biodiversity and Ecosystem Health of Ilhas Selvagens, Portugal |url=https://media.nationalgeographic.org/assets/file/PristineSeasSelvagensScientificReport.pdf |publisher=National Geographic Society |accessdate=4 November 2020}}</ref> The lakes in the image on the left are remnants of a single large lake, probably tens of kilometers long, that once occupied this remote area approximately 14,800 to 5,500 years ago. As the climate dried out during the subsequent millennia, the lake shrank, and large, wind-driven sand dunes invaded the original depression, dividing it into several smaller basins. The area shown in this image is approximately 11 by 9 kilometers. The lakes’ dark surfaces are almost completely segregated by linear, orange sand dunes that stream into the depression from the northeast. The almost-year-round northeast winds and cloudless skies make for very high evaporation rates; an evaporation rate of more than 6 meters per year has been measured in one of the nearby lakes. Despite this, only one of the ten lakes is saline. In the second image down on the right, the other Savage islands are ringed by bright white breaking waves along the fringing beaches. {{clear}} ==Reds== {{main|Radiation astronomy/Reds}} [[Image:Ankara, Turkey.jpg|thumb|right|250px|The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] The central portion of the capital city of Turkey, Ankara, is featured in this astronaut photograph. Hill slopes around the city (image left and right) are fairly green due to spring rainfall. One of the most striking aspects of the urban area is the almost uniform use of red brick roofing tiles, which contrast with lighter-coloured roads; the contrast is particularly evident in the northern (image lower left) and southern (image upper right) portions of the city. Numerous parks are visible as green patches interspersed within the red-roofed urban region. A region of cultivated fields in the western portion of the city (image centre) is a recreational farming area known as the Atatürk Forest Farm and Zoo—an interesting example of intentional preservation of a former land use within an urban area. {{clear}} ==Capes== [[Image:Cape canaveral.jpg|thumb|right|250px|Cape Canaveral, Florida, and the NASA John F. Kennedy Space Center are shown in this near-vertical photograph. Credit: NASA STS-43 crew.{{tlx|free media}}]] '''Def.''' a "piece or point of land, extending beyond the adjacent coast into a sea or lake"<ref name=CapeWikt>{{ cite book |title=cape |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2014 |url=https://en.wiktionary.org/wiki/cape |accessdate=2014-12-20 }}</ref> is called a '''cape'''. {{clear}} ==Coastlines== [[Image:Dalmatian Coastline near Split, Croatia.jpg|thumb|right|250px|Dalmatian Coastline near Split, Croatia, is shown. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] In this image on the right, a thin zone of disturbed water (tan patches) marking a water boundary appears in the Adriatic Sea between Split and the island of Brač. It may be a plankton bloom or a line of convergence between water masses, which creates rougher water. {{clear}} ==Craters== {{main|Radiation astronomy/Craters}} [[Image:ISS020-E-026195 Aorounga Impact Crater Chad.jpg|thumb|right|250px|The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Mount Tambora Volcano, Sumbawa Island, Indonesia.jpg|thumb|left|250px|This detailed astronaut photograph depicts the summit caldera of the Mount Tambora. Credit: NASA ISS Expedition 20 crew.{{tlx|free media}}]] The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph on the right. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. Aorounga Impact Crater is located in the Sahara Desert, in north-central Chad, and is one of the best preserved impact structures in the world. The crater is thought to be middle or upper Devonian to lower Mississippian (approximately 345–370 million years old) based on the age of the sedimentary rocks deformed by the impact. Spaceborne Imaging Radar (SIR) data collected in 1994 suggests that Aorounga is one of a set of three craters formed by the same impact event. The other two suggested impact structures are buried by sand deposits. The concentric ring structure of the Aorounga crater—renamed Aorounga South in the multiple-crater interpretation of SIR data—is clearly visible in this detailed astronaut photograph. The central highland, or peak, of the crater is surrounded by a small sand-filled trough; this in turn is surrounded by a larger circular trough. Linear rock ridges alternating with light orange sand deposits cross the image from upper left to lower right; these are called yardangs by geomorphologists. Yardangs form by wind erosion of exposed rock layers in a unidirectional wind field. The wind blows from the northeast at Aorounga, and sand dunes formed between the yardangs are actively migrating to the southwest. {{clear}} ==Glaciology== {{main|Radiation astronomy/Cryometeors}} [[Image:Upsala Glacier, Argentina.jpg|thumb|right|250px|The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. Credit: NASA Expedition 21 crew.{{tlx|free media}}]] The Southern Patagonian Icefield of Argentina and Chile is the southern remnant of the Patagonia Ice Sheet that covered the southern Andes Mountains during the last ice age. This detailed astronaut photograph on the right illustrates the terminus of one of the ice-field’s many spectacular glaciers—Upsala Glacier, located on the eastern side of the ice-field. This image was taken during spring in the Southern Hemisphere, and icebergs were calving from the glacier terminus into the waters of Lago Argentino (Lake Argentina, image right). Two icebergs are especially interesting because they retain fragments of the moraine (rock debris) that forms a dark line along the upper surface of the glacier. The inclusion of the moraine illustrates how land-based rocks and sediment may wind up in ocean sediments far from shore. Moraines are formed from rock and soil debris that accumulate along the front and sides of a flowing glacier. The glacier is like a bulldozer that pushes soil and rock in front of it, leaving debris on either side. When two glaciers merge (image centre), moraines along their edges can join to form a medial moraine that is drawn out along the upper surface of the new glacier. {{clear}} ==Lakes== [[Image:STS001-012-0363 - View of China (Retouched).tif|thumb|right|250px|View shows the lake Jieze Caka in Tibet. Credit: NASA STS-1 crew, [[c:user:Askeuhd|Askeuhd]].{{tlx|free media}}]] [[Image:STS002-13-274 - View of China.jpg|thumb|left|250px|The image shows Bangong Lake in Himalaya, China. Credit: STS-2 crew.{{tlx|free media}}]] '''Def.''' a "large, [landlocked]<ref name=LakeWikt1>{{ cite book |author=[[wikt:User:Paul G|Paul G]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=15 December 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> stretch of water"<ref name=LakeWikt>{{ cite book |author=[[wikt:User:Polyglot|Polyglot]] |title=lake |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=11 July 2003 |url=https://en.wiktionary.org/wiki/lake |accessdate=15 July 2022 }}</ref> is called a '''lake'''. The image on the right show the Tibetan plateau containing lake Jieze Caka. {{clear}} ==Mountains== [[Image:Saint Helena Island.jpg|thumb|250px|right|This astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. Credit: NASA Expedition 19 crew.{{tlx|free media}}]] '''Def.''' a "large mass of earth and rock, rising above the common level of the earth or adjacent land, usually given by geographers as above 1000 feet in height (or 304.8 metres), though such masses may still be described as hills in comparison with larger mountains"<ref name=MountainWikt>{{ cite book |author=[[wikt:User:92.7.198.35|92.7.198.35]] |title=mountain |publisher=Wikimedia Foundation, Inc |location=San Francisco, California |date=9 January 2011 |url=https://en.wiktionary.org/wiki/mountain |accessdate=2014-12-14 }}</ref> is called a '''mountain'''. The image on the right was acquired by astronauts onboard the International Space Station as part of an ongoing effort (the HMS Beagle Project) to document current biodiversity in areas visited by Charles Darwin. Saint Helena Island, located in the South Atlantic Ocean approximately 1,860 kilometers (1,156 miles) west of Africa, was one of the many isolated islands that naturalist Charles Darwin visited during his scientific voyages in the nineteenth century. He visited the island in 1836 aboard the HMS Beagle, recording observations of the plants, animals, and geology that would shape his theory of evolution. The astronaut photograph shows the island’s sharp peaks and deep ravines; the rugged topography results from erosion of the volcanic rocks that make up the island. The change in elevation from the coast to the interior creates a climate gradient. The higher, wetter center is covered with green vegetation, whereas the lower coastal areas are drier and hotter, with little vegetation cover. Human presence on the island has also caused dramatic changes to the original plants and animals of the island. Only about 10 percent of the forest cover observed by the first explorers now remains in a semi-natural state, concentrated in the interior highlands. {{clear}} ==Rock structures== {{main|Radiation astronomy/Rocks}} [[Image:Big Thomson Mesa, Capitol Reef National Park, Utah.jpg|thumb|right|250px|This detailed astronaut photograph shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] This detailed astronaut photograph on the right shows part of Big Thomson Mesa, near the southern end of Capitol Reef National Park. Capitol Reef National Park is located on the Colorado Plateau, which occupies the adjacent quarters of Arizona, Colorado, New Mexico, and Utah. Big Thomson Mesa (image left) is part of a large feature known as the en:Waterpocket Fold. The Fold is a geologic structure called a monocline—layers of generally flat-lying sedimentary rock with a steep, one-sided bend, like a carpet runner draped over a stair step. Geologists think that monoclines on the Colorado Plateau result from faulting (cracking) of deeper and more brittle crystalline rocks under tectonic pressure; while the crystalline rocks were broken into raised or lowered blocks, the overlaying, less brittle sedimentary rocks were flexed without breaking. The portion of the Waterpocket Fold illustrated in this image includes layered rocks formed during the Mesozoic Era (about 250 – 65 million years ago). The oldest layers are at the bottom of the sequence, with each successive layer younger than the preceding one going upwards in the sequence. Not all of the formation’s rock layers are clearly visible, but some of the major layers (units to geologists) can be easily distinguished. The top half of the image includes the oldest rocks in the view: dark brown and dark green Moenkopi and Chinle Formations. Moving toward the foot of the mesa, two strikingly coloured units are visible near image centre: light red to orange Wingate Sandstone and white Navajo Sandstone. Beyond those units, reddish brown to brown Carmel Formation and Entrada Sandstone occupy a topographic bench at the foot of a cliff. The top of the cliff face above this bench—Big Thomson Mesa—is comprised of brown Dakota Sandstone. This sequence represents more than 100 million years of sediments being deposited and turned into rock. Much younger Quaternary (2-million- to approximately 10,000-year-old) deposits are also present in the view. The area shown in this astronaut photograph is located approximately 65 kilometers to the southeast of Fruita, UT near the southern end of Capitol Reef National Park. {{clear}} ==Volcanoes== [[Image:Mount Hood, Oregon.jpg|thumb|right|250px|Gray volcanic deposits from Mount Hood extend southwards along the banks of the White River (image lower left). Credit: NASA Expedition 20 crew.{{tlx|free media}}]] [[Image:Teide Volcano, Canary Islands, Spain.jpg|thumb|left|250px|This detailed astronaut photograph features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island. Credit: NASA Expedition 20 crew.{{tlx|free media}}]] Gray volcanic deposits extend southwards along the banks of the White River (image lower left) and form several prominent ridges along the south-east to south-west flanks of the volcano. The deposits contrast sharply with the green vegetation on the lower flanks of the volcano. North is to the right. The detailed astronaut photograph on the left features two stratovolcanoes—Pico de Teide and Pico Viejo—located on Tenerife Island, part of the Canary Islands of Spain. Stratovolcanoes are steep-sided, typically conical volcanoes formed by interwoven layers of lava and fragmented rock material from explosive eruptions. Pico de Teide has a relatively sharp peak, whereas an explosion crater forms the summit of Pico Viejo. The two stratovolcanoes formed within an even larger volcanic structure known as the Las Cañadas caldera. A caldera is a large collapse depression usually formed when a major eruption completely empties the magma chamber underlying a volcano. The last eruption of Teide occurred in 1909. Sinuous flow levees marking individual lava flows are perhaps the most striking volcanic features visible in the image. Flow levees are formed when the outer edges of a channelized lava flow cool and harden while the still-molten interior continues to flow downhill. Numerous examples radiate outwards from the peaks of both Pico de Teide and Pico Viejo. Brown to tan overlapping lava flows and domes are visible to the east-south-east of the Teide stratovolcano. {{clear}} ==See also== {{div col|colwidth=20em}} * [[Radiation astronomy/Gravitationals|Gravitational astronomy]] * [[Radiation astronomy/Infrareds|Infrared astronomy]] * [[Radiation astronomy/Radars|Radar astronomy]] * [[Radio astronomy]] * [[Submillimeter astronomy]] * [[Radiation astronomy/Superluminals|Superluminal astronomy]] {{Div col end}} ==References== {{reflist|2}} ==External links== * [http://www.iau.org/ International Astronomical Union] * [http://nedwww.ipac.caltech.edu/ NASA/IPAC Extragalactic Database - NED] * [http://nssdc.gsfc.nasa.gov/ NASA's National Space Science Data Center] * [http://www.ncbi.nlm.nih.gov/sites/gquery NCBI All Databases Search] * [http://www.osti.gov/ Office of Scientific & Technical Information] * [http://www.ncbi.nlm.nih.gov/pccompound PubChem Public Chemical Database] * [http://www.adsabs.harvard.edu/ The SAO/NASA Astrophysics Data System] * [http://www.scirus.com/srsapp/advanced/index.jsp?q1= Scirus for scientific information only advanced search] * [http://cas.sdss.org/astrodr6/en/tools/quicklook/quickobj.asp SDSS Quick Look tool: SkyServer] * [http://simbad.u-strasbg.fr/simbad/ SIMBAD Astronomical Database] * [http://simbad.harvard.edu/simbad/ SIMBAD Web interface, Harvard alternate] * [http://nssdc.gsfc.nasa.gov/nmc/SpacecraftQuery.jsp Spacecraft Query at NASA] * [http://heasarc.gsfc.nasa.gov/cgi-bin/Tools/convcoord/convcoord.pl Universal coordinate converter] <!-- footer templates --> {{tlx|Principles of radiation astronomy}}{{Radiation astronomy resources}}{{Sisterlinks|Orbital platforms}} <!-- categories --> [[Category:Spaceflight]] rukf6p3d6l7ias4n4aqe7o2tm1ikse3 2 285215 2408239 2408101 2022-07-21T00:26:12Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} <br /><hr /> '''Web Resources''' * [https://www.sciencedaily.com/releases/2022/02/220218100644.htm ScienceDaily - Easy aluminum nanoparticles for rapid, efficient hydrogen generation from water] {{RoundBoxBottom}} <hr /> qa3wy9prw66omq8bzf897yhj402x7pc 2408244 2408239 2022-07-21T01:27:23Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by [[w:Bakthan Singaram|Professor Bakthan Singaram]] and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Stephens, Tim}} {{RoundBoxBottom}} <hr /> 746iltt7a4u4wmlgf788x9terzorih6 2408251 2408244 2022-07-21T01:50:19Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by Professor Singaram and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Stephens, Tim}} {{RoundBoxBottom}} <hr /> rvl8gp0xdz71kgk8rjb3pr27jetz43o 2408257 2408251 2022-07-21T02:52:44Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by Professor Singaram and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] * [https://www.youtube.com/watch?v=45bkmxE2srI 2012 BORAM-XIII Biennial Awards] [[File:High-contrast-camera-video.svg|24px|video]] (0:08:02) <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Stephens, Tim}} {{RoundBoxBottom}} <hr /> 2wwgb252rosvptme0fxkagarzwrl4xz 2408388 2408257 2022-07-21T07:17:26Z Jtwsaddress42 234843 /* Singaram, Bakthan */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Bakthan Singaram|Singaram, Bakthan]] === <hr /> [[File:Bakthan Singaram.jpg|thumb|Bakthan Singaram]] [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=singaram UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department - Faculty Professor Emerti] * <u>[https://singaram.chemistry.ucsc.edu/ Singaram Research Group]</u> - Singaram Research Group (SRG) at the University of California, Santa Cruz is headed by Professor Singaram and specializes in Boron-based organic chemistry. A primary goal of the Singaram lab is the development of novel chiral catalysts from terpenes, amino acids, and other biological and organic compounds. Bakthan is an expert in organic synthesis, organoborane chemistry, heterocyclic chemistry, organometallic chemistry, asymmetric synthesis, biosensors, and natural products chemistry. ** [https://www.sigmaaldrich.com/US/en/collections/professor-product-portal/singaram Sigma Alrich Portal] * [https://www.youtube.com/watch?v=45bkmxE2srI 2012 BORAM-XIII Biennial Awards] [[File:High-contrast-camera-video.svg|24px|video]] (0:08:02) <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Singaram et al.}} <br /><hr /> {| align= center |'''TarBX Reactions'''<br /> [[File:TarBX Reactions.png|640px|TarBX Reactions]] <br /> |} <hr /> {| align= center |'''LAB Reactions'''<br /> [[File:LAB Reagent.png|640px|LAB Reagent]]<br /> |} <hr /> {| align= center |'''Glucose Sensing Quencher-Dye System'''<br /> [[File:BoronicAcidDye.png|640px|BoronicAcidDye]]<br /> |} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Stephens, Tim}} {{RoundBoxBottom}} <hr /> 6pka1ttd23tt5szlw0imuh9jlsgfv0m 2 285294 2408248 2406251 2022-07-21T01:43:42Z Jtwsaddress42 234843 wikitext text/x-wiki Amberchan et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Amberchan, Gabriella}} Binder et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Binder, Caitlin M.}} Brown et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Brown, Herbert C.}} Chrisman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Chrisman, Will}} Clary et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Clary, Jacob W.}} Collins et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Collins, Christopher J.}} Eagon et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Eagon, Scott}} Gamsey et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Gamsey, Soya}} Goralski et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Goralski, Christian T.}} Haddad et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Haddad, Terra D.}} Hirayama et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hirayama, Lacie C.}} Kim et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Kim, Jinsoo}} Olmstead et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Olmstead, Marilyn M.}} Pasumansky et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Pasumansky, Lubov}} Schiller et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Schiller, Alexander}} Sharrett et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Sharrett, Zachary}} Steiner et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Steiner, Derek}} o6r3k980c1hb5j24z8wiu6ahhqnprv5 2 285305 2408376 2407269 2022-07-21T07:01:39Z Jtwsaddress42 234843 /* Mackie, George O. (1929 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:George_Owen_Mackie|Mackie, George O. (1929 - )]] === <hr /> {{User:Jtwsaddress42/Quotes/Mackie, George O. 1970a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Mackie, George O.}} {{RoundBoxBottom}} <hr /> b7m6mc2i389b30f0amhyqydcz8pyurr 2 285325 2408370 2408062 2022-07-21T06:56:45Z Jtwsaddress42 234843 /* Krishnamurti, Jiddu (1895-1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Jiddu Krishnamurti|Krishnamurti, Jiddu (1895-1986)]] === <hr /> [[File:Jiddu Krishnamurti 01.jpg|thumb|Jiddu Krishnamurti (1895-1986)]] '''Notable Accomplishments''' * Dissolved Theosophical "Order of the Star in the East" and renounced his role as a prophetic vehicle for the World Teacher. * Krishnamurti-Bohm Dialogs <br /> <hr /> {{User:Jtwsaddress42/Quotes/Krishnamurti, Jiddu 1969a}} {{User:Jtwsaddress42/Gallery/Jiddu Krishnamurti}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Krishnamurti, Jiddu}} {{RoundBoxBottom}} <hr /> ou99jtlxufwdqa3jhl7hxj2ri8cp2l0 2408371 2408370 2022-07-21T06:57:31Z Jtwsaddress42 234843 /* Krishnamurti, Jiddu (1895-1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Jiddu Krishnamurti|Krishnamurti, Jiddu (1895-1986)]] === <hr /> [[File:Jiddu Krishnamurti 01.jpg|thumb|Jiddu Krishnamurti (1895-1986)]] '''Notable Accomplishments''' * Dissolved Theosophical "Order of the Star in the East" and renounced his role as a prophetic vehicle for the World Teacher. * Krishnamurti-Bohm Dialogs <br /><hr /> {{User:Jtwsaddress42/Quotes/Krishnamurti, Jiddu 1969a}} {{User:Jtwsaddress42/Gallery/Jiddu Krishnamurti}} <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Krishnamurti, Jiddu}} {{RoundBoxBottom}} <hr /> obz2rxxqwkibqsz5kwhhdmpbjwlz33f 2 285343 2408369 2408061 2022-07-21T06:56:15Z Jtwsaddress42 234843 /* Kandel, Eric R. (1929-) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Eric Kandel|Kandel, Eric R. (1929-)]] === <hr /> [[File:Eric Kandel 1978.jpg|thumb|Eric Kandel 1978]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/2000/kandel/facts/ The Nobel Prize in Physiology or Medicine 2000 ] - shared with Arvid Carlsson and Paul Greengard “for their discoveries concerning signal transduction in the nervous system.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Kandel, Eric R.}} <br /><hr /> {{User:Jtwsaddress42/Bibliography/Kandel et al.}} {{RoundBoxBottom}} <hr /> 0ezoeyk2ujlzuhwxt02601jvb8bulpr 4 285346 2408254 2408144 2022-07-21T02:02:45Z Evolution and evolvability 922352 /* {{User|Eyoungstrom}} */ +s wikitext text/x-wiki === {{User|Eyoungstrom}} === [[User:Eyoungstrom|Eyoungstrom]] is being nominated by users [[User:Ncharamut|Ncharamut]] and [[User:Cody naccarato|Cody naccarato]]. He has been editing for over 7 years with a good track record of good-faith edits related to psychological information. He is associated with the non-profit HGAPS, and would help to monitor pages created by the group. He has successfully appealed to consensus, and has positive history with [[User:OhanaUnited|OhanaUnited]], [[User:Dave Braunschweig|Dave Braunschweig]], and [[User:Evolution and evolvability|Evolution and evolvability]]. Other Wiki affiliations include good editing history and civil discussions on Wikipedia. Eyoungstrom is also a member of the [[WikiJournal User Group]]. In this group, he has served as an editor for the [[WikiJournal of Medicine]], and is working to establish the [[WikiJournal of Psychology, Psychiatry and Behavioral Sciences]]. He is also a member of the [https://meta.wikimedia.org/wiki/North_Carolina_Wikipedians North Carolina Wikipedians user group] and the [https://meta.wikimedia.org/wiki/H-GAPS_User_Group HGAPS user group]. In all, we think his endorsement for curatorship will be a great asset to Wikiversity, which is supported by his suburb editing history and willingness to collaborate openly and fairly. This nomination comes as a suggestion from [[User:Dave Braunschweig|Dave Braunschweig]] to [[User:Ncharamut|Ncharamut]] as a result of recent vandalism across a few of HGAPS' wiki pages containing sensitive information. ==== Questions ==== ==== Comments ==== As I am completely out of my depth to make any judgement calls on anyone's nomination I can only say that what little I've read about the nomination and the candidate that he would be a worthy addition. [[User:Hamish84|Hamish84]] ([[User talk:Hamish84|discuss]] • [[Special:Contributions/Hamish84|contribs]]) 06:42, 19 July 2022 (UTC) ==== Voting ==== * {{support}} [[User:OhanaUnited|<b><span style="color: #0000FF;">OhanaUnited</span></b>]][[User talk:OhanaUnited|<b><span style="color: green;">^{Talk page}</span></b>]] 02:05, 16 July 2022 (UTC) * {{support}} --[[User:Marshallsumter|Marshallsumter]] ([[User talk:Marshallsumter|discuss]] • [[Special:Contributions/Marshallsumter|contribs]]) 02:21, 16 July 2022 (UTC) * {{support}} [[User:Bobbyshabangu|Bobbyshabangu]] ([[User talk:Bobbyshabangu|discuss]] • [[Special:Contributions/Bobbyshabangu|contribs]]) 13:49, 16 July 2022 (UTC) *{{support}} --[[User:Lbeaumont|Lbeaumont]] ([[User talk:Lbeaumont|discuss]] • [[Special:Contributions/Lbeaumont|contribs]]) 14:28, 17 July 2022 (UTC) *{{support}} --[[User:Bert Niehaus|Bert Niehaus]] ([[User talk:Bert Niehaus|discuss]] • [[Special:Contributions/Bert Niehaus|contribs]]) 10:01, 20 July 2022 (UTC) *{{support}} -- The scope of intended activities is in line with the on-wiki experience they have so far and learning the few additional tools they'll need shouldn't be a problem. [[User:Evolution and evolvability|T.Shafee(Evo&#65120;Evo)]]^{[[User talk:Evolution and evolvability|talk]]} 02:02, 21 July 2022 (UTC) 7r9bnoerrhi5g5637iswh1ok1xbltwh 2 285377 2408323 2407551 2022-07-21T06:13:49Z Jtwsaddress42 234843 /* Carlsson, Arvid (1923 - 2018) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Arvid Carlsson|Carlsson, Arvid (1923 - 2018)]] === [[File:Arvid Carlsson 2011a.jpg|thumb|Arvid Carlsson]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1999/blobel/facts/ The Nobel Prize in Physiology or Medicine 2000] -shared with Eric Kandel and Paul Greengard, "for their discoveries concerning signal transduction in the nervous system." <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Carlsson, Arvid}} {{RoundBoxBottom}} <hr /> pmsqwtrgalt4gxduhfco7isedo346f6 2408341 2408323 2022-07-21T06:33:51Z Jtwsaddress42 234843 /* Carlsson, Arvid (1923 - 2018) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Arvid Carlsson|Carlsson, Arvid (1923 - 2018)]] === <hr/> [[File:Arvid Carlsson 2011a.jpg|thumb|Arvid Carlsson]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1999/blobel/facts/ The Nobel Prize in Physiology or Medicine 2000] -shared with Eric Kandel and Paul Greengard, "for their discoveries concerning signal transduction in the nervous system." <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Carlsson, Arvid}} {{RoundBoxBottom}} <hr /> ncnzuuqk7f2ke4mrehm9r73kxrv9eyr 2 285382 2408372 2408064 2022-07-21T06:59:56Z Jtwsaddress42 234843 /* Lovelock, James E. (1919 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:James Lovelock|Lovelock, James E. (1919 - )]] === <hr /> [[File:James Lovelock in 2005.jpg|thumb|James_Lovelock]] [[File:James Lovelocks Electron capture detector for a gas chromatograph, 1960. (9660569973).jpg|thumb|James Lovelocks Electron capture detector for a gas chromatograph, 1960.]] '''Notable Accomplishments''' * Electron Capture Detector * Gaia Hypothesis <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Lovelock, James E.}} {{RoundBoxBottom}} <hr /> gcar1nf93xey1tg2pq7jzlkyco29fib 2 285403 2408333 2407541 2022-07-21T06:24:23Z Jtwsaddress42 234843 /* Blobel, Günter (1936 – 2018) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Günter Blobel|Blobel, Günter (1936 – 2018)]] === <hr /> [[File:Gunter Blobel 2008 1.JPG|thumb|Günter Blobel (1936 – 2018)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1999/blobel/facts/ The Nobel Prize in Physiology or Medicine 1999] - "for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell." <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Blobel, Günter}} <hr /> Lingappa et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lingappa, Vishwanath R.}} {{RoundBoxBottom}} <hr /> 4csg2wcied3xhh4f25oiajliv97ugf4 2 285408 2408362 2407731 2022-07-21T06:51:20Z Jtwsaddress42 234843 /* Greengard, Paul (1925 - 2019) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Paul Greengard|Greengard, Paul (1925 - 2019)]] === <hr /> [[File:Paul Greengard.jpg|thumb|Paul Greengard (1925 - 2019)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/2000/greengard/facts/ The Nobel Prize in Physiology or Medicine 2000] - shared with Arvid Carlsson and Eric R. Kandel "for their discoveries concerning signal transduction in the nervous system." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Greengard, Paul}} {{RoundBoxBottom}} <hr /> 81ulp1hlfz1vfvhx7zlefeenwiqnxyj 2408363 2408362 2022-07-21T06:51:34Z Jtwsaddress42 234843 /* Greengard, Paul (1925 - 2019) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Paul Greengard|Greengard, Paul (1925 - 2019)]] === <hr /> [[File:Paul Greengard.jpg|thumb|Paul Greengard (1925 - 2019)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/2000/greengard/facts/ The Nobel Prize in Physiology or Medicine 2000] - shared with Arvid Carlsson and Eric R. Kandel "for their discoveries concerning signal transduction in the nervous system." <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Greengard, Paul}} {{RoundBoxBottom}} <hr /> cvvu9ddldth7ra1or6pqfmyl16d0keh 2 285413 2408354 2408117 2022-07-21T06:45:37Z Jtwsaddress42 234843 /* Mircéa Éliade (1907 - 1986) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Mircea_Eliade|Mircéa Éliade (1907 - 1986)]] === <hr /> [[File:Mircea Eliade young.jpg|thumb|Éliade, Mircéa (1907 - 1986)]] '''Notable Accomplishments''' * The History of Alchemy, Shamanism, and other Religious Modes <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Éliade, Mircéa}} <br /><hr /> {{User:Jtwsaddress42/Gallery/Mircéa Éliade}} {{RoundBoxBottom}} <hr /> 2f4pnh4gfozm0nr6qjniw86d6a343q1 2 285430 2408368 2408060 2022-07-21T06:55:23Z Jtwsaddress42 234843 /* Jerne, Niels K. (1911 - 1994) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Niels K. Jerne|Jerne, Niels K. (1911 - 1994)]] === <hr /> [[File:Niels Kaj Jerne 1950 crop.jpg|thumb|Niels Kaj Jerne]] [[File:Niels Kaj Jerne 1950.jpg|thumb|Maaløe, Jerne, & Watson 1950{{efn|Niels K. Jerne was assistant to Ole Maaløe at Statens Seruminstitut. This photo of 1950, taken from Jernes' private collection, shows Maaløe in the middle with a pipe and Jerne at the window; the DNA discoverer James Watson sits in front of him.}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/medicine/1984/jerne/facts/ The Nobel Prize in Physiology or Medicine 1984] - shared with Georges J.F. Köhler and César Milstein “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Jerne, Niels K.}} {{RoundBoxBottom}} <hr /> psx281cclqm5duwdtw6awpdrrazxd68 2 285433 2408381 2407266 2022-07-21T07:05:43Z Jtwsaddress42 234843 /* Morris, Simon Conway (1951 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Simon Conway Morris|Morris, Simon Conway (1951 - )]] === <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Morris, Simon Conway}} {{RoundBoxBottom}} <hr /> nsi08m8i6wscfzbgsnajqnuetzmueuk 2 285469 2408277 2408058 2022-07-21T04:49:41Z Jtwsaddress42 234843 /* Negishi, Ei-ichi (1935 - 2021) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ei-ichi Negishi|Negishi, Ei-ichi (1935 - 2021)]] === [[File:Nobel Prize 2010-Press Conference KVA-DSC 7398.jpg|thumb|Ei-ichi Negishi (1935 - 2021){{efn|Nobel Prize 2010-Press Conference KVA-DSC 7398}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/negishi/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis.” <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Negishi, Ei-ichi}} <hr /> {| align= center |'''Pd & Ni Catalytic Cycles for Negishi Reaction'''<br /> [[File:NegishiScheme1.png]]<br /> |- |''Palladium Mechanism'' [[File:Scheme2Catcycle.png|640px|Scheme2Catcycle]] <br /><br /> |- |''Nickel Mechanism'' [[File:NickelMechanism.png|NickelMechanism]] |} {{RoundBoxBottom}} <hr /> 58r9lqaxvie97ke5s4d1ax8lwduyxpe 2408383 2408277 2022-07-21T07:07:29Z Jtwsaddress42 234843 /* Negishi, Ei-ichi (1935 - 2021) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Ei-ichi Negishi|Negishi, Ei-ichi (1935 - 2021)]] === <hr /> [[File:Nobel Prize 2010-Press Conference KVA-DSC 7398.jpg|thumb|Ei-ichi Negishi (1935 - 2021){{efn|Nobel Prize 2010-Press Conference KVA-DSC 7398}}]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/negishi/facts/ The Nobel Prize in Chemistry 2010] - shared with Richard Heck and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis.” <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Negishi, Ei-ichi}} <hr /> {| align= center |'''Pd & Ni Catalytic Cycles for Negishi Reaction'''<br /> [[File:NegishiScheme1.png]]<br /> |- |''Palladium Mechanism'' [[File:Scheme2Catcycle.png|640px|Scheme2Catcycle]] <br /><br /> |- |''Nickel Mechanism'' [[File:NickelMechanism.png|NickelMechanism]] |} {{RoundBoxBottom}} <hr /> lrysvk9xn6c7fyz7unlsmxhyzzuqcp8 2 285471 2408337 2408102 2022-07-21T06:29:58Z Jtwsaddress42 234843 /* Brown, Herbert C. (1912 - 2004) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Herbert C. Brown|Brown, Herbert C. (1912 - 2004)]] === <hr /> [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1979/brown/facts/ The Nobel Prize in Chemistry 1979] - shared with [[w:George Wittig|George Wittig]], "for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis." <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Brown, Herbert C.}} {{RoundBoxBottom}} <hr /> jeayswrxczc38hnmt28c88w90l4b4ad 2408338 2408337 2022-07-21T06:30:13Z Jtwsaddress42 234843 /* Brown, Herbert C. (1912 - 2004) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Herbert C. Brown|Brown, Herbert C. (1912 - 2004)]] === <hr /> [[File:Structural formula of (+)-Diisopinocampheylborane.svg|thumb|(+)-Diisopinocampheylborane]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/1979/brown/facts/ The Nobel Prize in Chemistry 1979] - shared with [[w:George Wittig|George Wittig]], "for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis." <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Brown, Herbert C.}} {{RoundBoxBottom}} <hr /> kc0grk6z4fsph66d62rubgxkjc8shx2 2 285472 2408367 2408057 2022-07-21T06:54:29Z Jtwsaddress42 234843 /* Heck, Richard F. (1931 - 2015) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Richard F. Heck|Heck, Richard F. (1931 - 2015)]] === <hr /> [[File:Richard F. Heck2010.jpg|thumb|Richard F. Heck (1931 - 2015)]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2010/heck/facts/ The Nobel Prize in Chemistry 2010] - shared with Ei-ichi Negishi and Akira Suzuki “for palladium-catalyzed cross couplings in organic synthesis.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Heck, Richard F.}} <br /><hr /> {| align = center |'''Heck Mechanism'''<br /> [[File:Heck mechanism.png|640px|Heck mechanism]] <br /><br /> |- |'''Reductive Heck vs. Classical Mizoroki–Heck Mechanism'''<br /> [[File:Reductive Heck vs. Classical Mizoroki–Heck Mechanism.png|640px|Reductive_Heck_vs._Classical_Mizoroki–Heck_Mechanism]] <br /> |} {{RoundBoxBottom}} <hr /> 7cuy8gme33oyify49qyudqv7bl9q8vo 2 285475 2408373 2408063 2022-07-21T07:00:29Z Jtwsaddress42 234843 /* Lefkowitz, Robert J. (1943 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Robert J. Lefkowitz|Lefkowitz, Robert J. (1943 - )]] === <hr /> [[File:Robert Lefkowitz 2 2012.jpg|thumb|Robert Lefkowitz]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/ The Nobel Prize in Chemistry 2012] - shared with Brian K. Kobilka “for studies of G-protein-coupled receptors.” <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Lefkowitz, Robert J.}} {{RoundBoxBottom}} <hr /> mzkjysshyl5folbqxgs66ladyqi5kve 2408374 2408373 2022-07-21T07:00:42Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Robert J. Lefkowitz|Lefkowitz, Robert J. (1943 - )]] === <hr /> [[File:Robert Lefkowitz 2 2012.jpg|thumb|Robert Lefkowitz]] '''Notable Accomplishments''' * [https://www.nobelprize.org/prizes/chemistry/2012/lefkowitz/facts/ The Nobel Prize in Chemistry 2012] - shared with Brian K. Kobilka “for studies of G-protein-coupled receptors.” <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Lefkowitz, Robert J.}} {{RoundBoxBottom}} <hr /> c5jsqj18e07kma6xhpnsnulojfm56bo 4 285491 2408220 2408042 2022-07-20T20:33:43Z Alexis Jazz 791434 Updating gadget usage statistics from [[Special:GadgetUsage]] ([[phab:T121049]]) wikitext text/x-wiki {{#ifexist:Project:GUS2Wiki/top|{{/top}}|This page provides a historical record of [[Special:GadgetUsage]] through its page history. To get the data in CSV format, see wikitext. To customize this message or add categories, create [[/top]].}} The following data is cached, and was last updated 2022-07-20T00:19:04Z. A maximum of {{PLURAL:5000|one result is|5000 results are}} available in the cache. {| class="sortable wikitable" ! Gadget !! data-sort-type="number" | Number of users !! data-sort-type="number" | Active users |- |EnhancedTalk || 1303 || 4 |- |HideFundraisingNotice || 748 || 6 |- |HotCat || 815 || 12 |- |Round Corners || 1107 || 4 |- |contribsrange || 347 || 2 |- |dark-mode || 14 || 1 |- |dark-mode-toggle || 27 || 4 |- |edittop || 457 || 8 |- |popups || 788 || 4 |- |purge || 663 || 7 |- |sidebartranslate || 496 || 2 |} * [[Special:GadgetUsage]] * [[w:en:Wikipedia:GUS2Wiki/Script|GUS2Wiki]] <!-- data in CSV format: EnhancedTalk,1303,4 HideFundraisingNotice,748,6 HotCat,815,12 Round Corners,1107,4 contribsrange,347,2 dark-mode,14,1 dark-mode-toggle,27,4 edittop,457,8 popups,788,4 purge,663,7 sidebartranslate,496,2 --> 116grq4h6s6fmbpisxpsodzpcd9p23e 0 285519 2408202 2022-07-20T18:29:12Z Hamish84 1362807 Started new document wikitext text/x-wiki [[File:Aleksis Kivi silhouette.png|left|thumb]] [[File:Bernhard Albrecht Moll Franz Boos.jpg|center|thumb]] Giving credence to the possibility of division directly impinges negatively on any possible experience of Reality as a whole experience. All principles that we recognize as implicit standards in making Reality transparent (Archimedes--the principle of leverage et al.) are good testaments to the direct relationship between the knower, and the known. In this regard, complementary evident proof of realisation (the principle of leverage et al.) can stand as markers to our innate ability to recognize consistent standards eventually. It is the quality of our inevitable experiences that dictates our ability to relate to ‘what is’. Conventionally we have presumed that our only means of defining ‘what is’ is generated by thought processes, and we have invested a great deal of human capital into securing that modus operandi as the only way of experiencing Reality. Equity means balance. Balance means agreement. Agreement means equity. The implicit ‘wholeness’ of all principles or absolutes lies in the fact that they are equally interchangeable. Reality is not composed of definitive answers - it is what it is. Final answers act as stepping-stones toward real experience. When we cling to mind as the repository for actual knowledge, we then automatically set up a firewall to exclude any threat to its existence. It is the so-called ’mind’ that demands an exercise or involvement in some futile effort which propagates ‘more reasonable’ intractable theories. I experience, you experience, we all experience. To experience complete microscopic acts cannot be done in isolation. We do not observe in isolation; there must be connectedness. The Reality of the full microscopic action is that it has connectedness with the macrocosm in that it has all the implicit information necessary to provide us guidance (principle of leverage et al.). You may liken the experience of realising the properties of a grain of sand. In that instance, you then experience the stuff of every grain of sand. So to extend the analogy, if we experience the complete innate properties of a human being, we share the essential properties of every human being. It is our fundamental connectedness, and it bestows on us the potential ability to identify wholly, and ultimately ‘who we are’. If it were not within our innate capacity to know ‘who we are’, life, as we live it in contact with other homo sapiens, would be an impossible nightmare! Implicit within that pure experience, everything is. Because there are constants, we can keep at least a tenuous grip on reality.” Observe human conformity at all levels, and there is the possibility that you will see that spatial dimension (expanse) in which all exist. That vision is not mind centred; it is part of the external spectrum. Instead of attempting to negate our very existence, let philosophy take its rightful place and address ‘what is’. The truth concerning the principle of leverage, measurements, etc., are not the personal property of Archimedes, or anyone else. They are Universal properties that we all equally share and consistently use. Principles do exist (experience understood), and it does not require a ‘mind’ or ‘consciousness’ to establish their Reality, however much you apply a ‘more reasonable’ standard of knowledge of their existence. All anyone can ever see is Reality in all its manifest forms. Never to see the principles operating in that Natural macrocosm is indeed a human tragedy. Reality is the principle - thought is a fictitious dichotomy. Whatever the truth that exists in Reality, we must learn to measure it. There is nothing else. The human experience is premised on how we exist and concur with the principles of Nature. Despite that inescapable necessity, we seem to continue along a path that attempts to deny that we are of the properties of Nature. Our very appearance and existence are corrupted by a ‘mind’ that intrudes itself into our everyday operations and distorts the reality that exists. Any proposition put forward based on the existence of a ‘mind’ must inevitably be flawed if any knowledge base lies in a restricted mythical location. The error comes about through believing that thought is an irrefutable process that can provide solutions. In effect, when we experience ‘that which is’ then the illusion (belief) is destroyed, and the illusory ‘I’ goes with it. In that circumstance, any question on the existence of Reality, Nature, Wholeness, is irrelevant. We can point to all Matter, all Energy, all Space, and all Time, as being objective imperatives without imposing any personal claim on their existence. The mind is an ‘I am’ delusional concept that for its protection, refuses to admit the externality of Reality, and of who ‘we are’. That Reality is not an incorporated projection of an individual imaginary life, but the vibrant relationship with everything that is. Our constant engagement with Science, Art, Education, Industry, etc., is testament to that relationship, and our adherence to the innate principles contained in Nature and ourselves. It is not ‘minds’ that ‘think alike’ to be aware of Reality; it is the experience of that which is true. We have the opportunity then to engage with their absolute intrinsic principles (the stuff of the Universe) of which we are the beneficiaries, and realise that personal relationship.” 7o0adz37y2ne5kc80c09h034zn1xkt6 2408203 2408202 2022-07-20T18:31:03Z Hamish84 1362807 Balancing text wikitext text/x-wiki [[File:Aleksis Kivi silhouette.png|left|thumb]] [[File:Bernhard Albrecht Moll Franz Boos.jpg|center|thumb]] Giving credence to the possibility of division directly impinges negatively on any possible experience of Reality as a whole experience. All principles that we recognize as implicit standards in making Reality transparent (Archimedes--the principle of leverage et al.) are good testaments to the direct relationship between the knower, and the known. In this regard, complementary evident proof of realisation (the principle of leverage et al.) can stand as markers to our innate ability to recognize consistent standards eventually. It is the quality of our inevitable experiences that dictates our ability to relate to ‘what is’. Conventionally we have presumed that our only means of defining ‘what is’ is generated by thought processes, and we have invested a great deal of human capital into securing that modus operandi as the only way of experiencing Reality. Equity means balance. Balance means agreement. Agreement means equity. The implicit ‘wholeness’ of all principles or absolutes lies in the fact that they are equally interchangeable. Reality is not composed of definitive answers - it is what it is. Final answers act as stepping-stones toward real experience. When we cling to mind as the repository for actual knowledge, we then automatically set up a firewall to exclude any threat to its existence. It is the so-called ’mind’ that demands an exercise or involvement in some futile effort which propagates ‘more reasonable’ intractable theories. I experience, you experience, we all experience. To experience complete microscopic acts cannot be done in isolation. We do not observe in isolation; there must be connectedness. The Reality of the full microscopic action is that it has connectedness with the macrocosm in that it has all the implicit information necessary to provide us guidance (principle of leverage et al.). You may liken the experience of realising the properties of a grain of sand. In that instance, you then experience the stuff of every grain of sand. So to extend the analogy, if we experience the complete innate properties of a human being, we share the essential properties of every human being. It is our fundamental connectedness, and it bestows on us the potential ability to identify wholly, and ultimately ‘who we are’. If it were not within our innate capacity to know ‘who we are’, life, as we live it in contact with other homo sapiens, would be an impossible nightmare! Implicit within that pure experience, everything is. Because there are constants, we can keep at least a tenuous grip on reality.” Observe human conformity at all levels, and there is the possibility that you will see that spatial dimension (expanse) in which all exist. That vision is not mind centred; it is part of the external spectrum. Instead of attempting to negate our very existence, let philosophy take its rightful place and address ‘what is’. The truth concerning the principle of leverage, measurements, etc., are not the personal property of Archimedes, or anyone else. They are Universal properties that we all equally share and consistently use. Principles do exist (experience understood), and it does not require a ‘mind’ or ‘consciousness’ to establish their Reality, however much you apply a ‘more reasonable’ standard of knowledge of their existence. All anyone can ever see is Reality in all its manifest forms. Never to see the principles operating in that Natural macrocosm is indeed a human tragedy. Reality is the principle - thought is a fictitious dichotomy. Whatever the truth that exists in Reality, we must learn to measure it. There is nothing else. The human experience is premised on how we exist and concur with the principles of Nature. Despite that inescapable necessity, we seem to continue along a path that attempts to deny that we are of the properties of Nature. Our very appearance and existence are corrupted by a ‘mind’ that intrudes itself into our everyday operations and distorts the reality that exists. Any proposition put forward based on the existence of a ‘mind’ must inevitably be flawed if any knowledge base lies in a restricted mythical location. The error comes about through believing that thought is an irrefutable process that can provide solutions. In effect, when we experience ‘that which is’ then the illusion (belief) is destroyed, and the illusory ‘I’ goes with it. In that circumstance, any question on the existence of Reality, Nature, Wholeness, is irrelevant. We can point to all Matter, all Energy, all Space, and all Time, as being objective imperatives without imposing any personal claim on their existence. The mind is an ‘I am’ delusional concept that for its protection, refuses to admit the externality of Reality, and of who ‘we are’. That Reality is not an incorporated projection of an individual imaginary life, but the vibrant relationship with everything that is. Our constant engagement with Science, Art, Education, Industry, etc., is testament to that relationship, and our adherence to the innate principles contained in Nature and ourselves. It is not ‘minds’ that ‘think alike’ to be aware of Reality; it is the experience of that which is true. We have the opportunity then to engage with their absolute intrinsic principles (the stuff of the Universe) of which we are the beneficiaries, and realise that personal relationship.” s0mt63jlm4uuhq5cdvvoogkrcu9ugb9 2408318 2408203 2022-07-21T06:02:17Z Hamish84 1362807 Moving images wikitext text/x-wiki Identity [[File:Bernhard Albrecht Moll Franz Boos.jpg|thumb|left|[[File:John Leamy silhouette (University of California version, retouched).jpg|thumb]]]] [[File:Cooke silhouette.png|thumb]] Giving credence to the possibility of division directly impinges negatively on any possible experience of Reality as a whole experience. All principles that we recognize as implicit standards in making Reality transparent (Archimedes--the principle of leverage et al.) are good testaments to the direct relationship between they who know and the known. In this regard, complementary evident proof of realisation (the principle of leverage et al.) can stand as markers to our innate ability to recognize consistent standards eventually. It is the quality of our inevitable experiences that dictates our ability to relate to ‘what is’. Conventionally we have presumed that our only means of defining ‘what is’ is generated by thought processes, and we have invested a great deal of human capital into securing that modus operandi as the only way of experiencing Reality. Equity means balance. Balance means agreement. Agreement means equity. The implicit ‘wholeness’ of all principles or absolutes lies in the fact that they are equally interchangeable. Reality is not composed of definitive answers - it is what it is. Final answers act as stepping-stones toward real experience. When we cling to mind as the repository for actual knowledge, we then automatically set up a firewall to exclude any threat to its existence. It is the so-called ’mind’ that demands an exercise or involvement in some futile effort which propagates ‘more reasonable’ intractable theories. I experience, you experience, we all experience. To experience complete microscopic acts cannot be done in isolation. We do not observe in isolation; there must be connectedness. The Reality of the full microscopic action is that it has connectedness with the macrocosm in that it has all the implicit information necessary to provide us guidance (principle of leverage et al.). You may liken the experience of realising the properties of a grain of sand. In that instance, you then experience the stuff of every grain of sand. So to extend the analogy, if we experience the complete innate properties of a human being, we share the essential properties of every human being. It is our fundamental connectedness, and it bestows on us the potential ability to identify wholly, and ultimately ‘who we are’. If it were not within our innate capacity to know ‘who we are’, life, as we live it in contact with other homo sapiens, would be an impossible nightmare! Implicit within that pure experience, everything is. Because there are constants, we can keep at least a tenuous grip on reality.” Observe human conformity at all levels, and there is the possibility that you will see that spatial dimension (expanse) in which all exist. That vision is not mind centred; it is part of the external spectrum. Instead of attempting to negate our very existence, let philosophy take its rightful place and address ‘what is’. The truth concerning the principle of leverage, measurements, etc., are not the personal property of Archimedes, or anyone else. They are Universal properties that we all equally share and consistently use. Principles do exist (experience understood), and it does not require a ‘mind’ or ‘consciousness’ to establish their Reality, however much you apply a ‘more reasonable’ standard of knowledge of their existence. All anyone can ever see is Reality in all its manifest forms. Never to see the principles operating in that Natural macrocosm is indeed a human tragedy. Reality is the principle - thought is a fictitious dichotomy. Whatever the truth that exists in Reality, we must learn to measure it. There is nothing else. The human experience is premised on how we exist and concur with the principles of Nature. Despite that inescapable necessity, we seem to continue along a path that attempts to deny that we are of the properties of Nature. Our very appearance and existence are corrupted by a ‘mind’ that intrudes itself into our everyday operations and distorts the reality that exists. Any proposition put forward based on the existence of a ‘mind’ must inevitably be flawed if any knowledge base lies in a restricted mythical location. The error comes about through believing that thought is an irrefutable process that can provide solutions. In effect, when we experience ‘that which is’ then the illusion (belief) is destroyed, and the illusory ‘I’ goes with it. In that circumstance, any question on the existence of Reality, Nature, Wholeness, is irrelevant. We can point to all Matter, all Energy, all Space, and all Time, as being objective imperatives without imposing any personal claim on their existence. The mind is an ‘I am’ delusional concept that for its protection, refuses to admit the externality of Reality, and of who ‘we are’. That Reality is not an incorporated projection of an individual imaginary life, but the vibrant relationship with everything that is. Our constant engagement with Science, Art, Education, Industry, etc., is testament to that relationship, and our adherence to the innate principles contained in Nature and ourselves. It is not ‘minds’ that ‘think alike’ to be aware of Reality; it is the experience of that which is true. We have the opportunity then to engage with their absolute intrinsic principles (the stuff of the Universe) of which we are the beneficiaries, and realise that personal relationship.” gcgn7avxveuof8rkq74tn37w9t08mrp 2 285521 2408243 2022-07-21T01:26:41Z Jtwsaddress42 234843 New resource with "* {{ cite journal | last= Stephens | first= Tim | year= 2022 | title= Easy aluminum nanoparticles for rapid, efficient hydrogen generation from water | series= Science News - University of California - Santa Cruz | journal= ScienceDaily | publication-date= February 18, 2022 | url= https://www.sciencedaily.com/releases/2022/02/220218100644.htm }}" wikitext text/x-wiki * {{ cite journal | last= Stephens | first= Tim | year= 2022 | title= Easy aluminum nanoparticles for rapid, efficient hydrogen generation from water | series= Science News - University of California - Santa Cruz | journal= ScienceDaily | publication-date= February 18, 2022 | url= https://www.sciencedaily.com/releases/2022/02/220218100644.htm }} g6w8b265ehrru1uweymge8rb9s6p59u 2408256 2408243 2022-07-21T02:24:21Z Jtwsaddress42 234843 wikitext text/x-wiki * {{ cite journal | last= Stephens | first= Tim | year= 2022a | title= Easy aluminum nanoparticles for rapid, efficient hydrogen generation from water | series= Science News - University of California - Santa Cruz | journal= ScienceDaily | publication-date= February 18, 2022 | url= https://www.sciencedaily.com/releases/2022/02/220218100644.htm }} * {{ cite AV media | last= Stephens | first= Tim | year= 2022b | title= Easy aluminum nanoparticles for rapid, efficient hydrogen generation from water | publisher= Today's Sciencology | publication-date= February 19, 2022 | url= https://www.youtube.com/watch?v=QC9HzI3aM_0 }} [[File:High-contrast-camera-video.svg|24px|video]] (0:04:16) 7hprz6elsrnuvbljzks9p1tzpkhnz2y 2 285522 2408247 2022-07-21T01:42:21Z Jtwsaddress42 234843 New resource with "* {{cite journal | last1= Amberchan | first1= Gabriella | last2= Lopez | first2= Isai | last3= Ehlke | first3= Beatriz | last4= Barnett | first4= Jeremy | last5= Bao | first5= Neo Y. | last6= Allen | first6= A’Lester | last7= Singaram | first7= Bakthan | last8= Oliver | first8= Scott R. J. | year= 2022 | title= Aluminum Nanoparticles from a Ga–Al Composite for Water Splitting and Hydrogen Generation | journal= ACS Applied Nano Materials | volume= 5 | number= 2 | page..." wikitext text/x-wiki * {{cite journal | last1= Amberchan | first1= Gabriella | last2= Lopez | first2= Isai | last3= Ehlke | first3= Beatriz | last4= Barnett | first4= Jeremy | last5= Bao | first5= Neo Y. | last6= Allen | first6= A’Lester | last7= Singaram | first7= Bakthan | last8= Oliver | first8= Scott R. J. | year= 2022 | title= Aluminum Nanoparticles from a Ga–Al Composite for Water Splitting and Hydrogen Generation | journal= ACS Applied Nano Materials | volume= 5 | number= 2 | pages= 2636–2643 | publication-date= February 14, 2022 | doi= 10.1021/acsanm.1c04331 | url= https://pubs.acs.org/doi/10.1021/acsanm.1c04331 }} 67s9biou8xorgfvs16jby7b4vvcy0ju 2 285523 2408258 2022-07-21T03:52:50Z Jtwsaddress42 234843 New resource with "{{RoundBoxTop|theme=3}} === [https://millhauser.chemistry.ucsc.edu/ Millhauser, Glenn] === '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair * The Millhauser Lab uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser,..." wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://millhauser.chemistry.ucsc.edu/ Millhauser, Glenn] === '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair * The Millhauser Lab uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <br /> <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser, Glenn}} {{RoundBoxBottom}} <hr /> 3lpjw9k7s2esa7ww75nm05inx3cbwpa 2408260 2408258 2022-07-21T03:54:34Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://millhauser.chemistry.ucsc.edu/ Millhauser, Glenn] === '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair * The Millhauser Lab uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser, Glenn}} {{RoundBoxBottom}} <hr /> 57pbjecr2d8up5e1oxdytbj88c9z8u7 2408261 2408260 2022-07-21T03:55:10Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [https://millhauser.chemistry.ucsc.edu/ Millhauser, Glenn] === '''Notable Accomplishments''' * UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair * The Millhauser Lab uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser, Glenn}} {{RoundBoxBottom}} <hr /> 71xhposoez32i0hwk1deet9sj5idswy 2408263 2408261 2022-07-21T04:08:58Z Jtwsaddress42 234843 /* Millhauser, Glenn */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Glenn Millhauser|Millhauser, Glenn]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=glennm UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair] * [https://millhauser.chemistry.ucsc.edu/ The Millhauser Lab] uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser, Glenn}} {{RoundBoxBottom}} <hr /> 4202yuxoh3ld09e7aq7b7d7w4pihz8j 2408380 2408263 2022-07-21T07:05:02Z Jtwsaddress42 234843 /* Millhauser, Glenn */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Glenn Millhauser|Millhauser, Glenn]] === <hr /> '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=glennm UCSC Physical & Biological Sciences Division, Chemistry & Biochemistry Department, Faculty Distinguished Professor - Department Chair] * [https://millhauser.chemistry.ucsc.edu/ The Millhauser Lab] uses biophysical methods to study neurological proteins, their cofactors and how misregulation contributes to disease. <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Millhauser, Glenn}} {{RoundBoxBottom}} <hr /> n59ce8zxohmoywf3pm5xbq8ivsti8jk 2 285524 2408265 2022-07-21T04:19:39Z Jtwsaddress42 234843 New resource with "{{RoundBoxTop|theme=3}} === [[w:Harry Noller|Noller, Harry F.]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=hnoller UCSC Physical & Biological Sciences Division, Molecular, Cell, & Developmental Biology Department, Faculty Professor - Director, Center for Molecular Biology of RNA] <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Noller, Harry F.}} {{RoundBoxBottom}} <hr />" wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harry Noller|Noller, Harry F.]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=hnoller UCSC Physical & Biological Sciences Division, Molecular, Cell, & Developmental Biology Department, Faculty Professor - Director, Center for Molecular Biology of RNA] <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Noller, Harry F.}} {{RoundBoxBottom}} <hr /> pigjmsfs8es625nljrttaf5d8mmdt7j 2408268 2408265 2022-07-21T04:22:10Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harry F. Noller|Noller, Harry F.]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=hnoller UCSC Physical & Biological Sciences Division, Molecular, Cell, & Developmental Biology Department, Faculty Professor - Director, Center for Molecular Biology of RNA] * Ribosome structural and functional determination <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Noller, Harry F.}} {{RoundBoxBottom}} <hr /> i6tlku7z2vm2bdksmagcfjywxi7tpqt 2408275 2408268 2022-07-21T04:44:45Z Jtwsaddress42 234843 /* Noller, Harry F. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harry F. Noller|Noller, Harry F.]] === '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=hnoller UCSC Physical & Biological Sciences Division, Molecular, Cell, & Developmental Biology Department, Faculty Professor - Director, Center for Molecular Biology of RNA] * Ribosome structural and functional determination <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Noller, Harry F.}} <hr /> Green et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Green, Rachel}} {{RoundBoxBottom}} <hr /> jprajm9r130f98r2hvjakup4tr24ony 2408384 2408275 2022-07-21T07:07:55Z Jtwsaddress42 234843 /* Noller, Harry F. */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Harry F. Noller|Noller, Harry F.]] === <hr /> '''Notable Accomplishments''' * [https://campusdirectory.ucsc.edu/cd_detail?uid=hnoller UCSC Physical & Biological Sciences Division, Molecular, Cell, & Developmental Biology Department, Faculty Professor - Director, Center for Molecular Biology of RNA] * Ribosome structural and functional determination <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Noller, Harry F.}} <hr /> Green et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Green, Rachel}} {{RoundBoxBottom}} <hr /> l2jrhhejiwqz4l5ly5cmaqzdxx28u2b 2 285525 2408279 2022-07-21T04:55:14Z Jtwsaddress42 234843 New resource with "{{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === '''Notable Accomplishments''' * <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <br /> '''Related''' {{RoundBoxBottom}} <hr />" wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === '''Notable Accomplishments''' * <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <br /> '''Related''' {{RoundBoxBottom}} <hr /> 6f7aw44htnir7o4m5jdgjw7kqi4l8gg 2408285 2408279 2022-07-21T05:08:29Z Jtwsaddress42 234843 /* Chomsky, Noam (1929 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === '''Notable Accomplishments''' * <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <br /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} {{RoundBoxBottom}} <hr /> n771gaai2n9osq7rm7s18djtnew21m7 2408305 2408285 2022-07-21T05:34:41Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === '''Notable Accomplishments''' * <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> h6uwv05uvbp1k3gtxvuo2mm9el41frb 2408306 2408305 2022-07-21T05:35:44Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] '''Notable Accomplishments''' * <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> o153xe9tqfuwtlw7dpkz0la1edbom30 2408307 2408306 2022-07-21T05:37:19Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> 73h6ga52dfm1yuk27vhypv4fxwdknfu 2408310 2408307 2022-07-21T05:49:22Z Jtwsaddress42 234843 /* Chomsky, Noam (1929 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] [[File:Noam Chomsky signature.svg|thumb]] [[File:Chomsky-hierarchy.svg|thumb|Chomsky-hierarchy]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy * Socialist-Libertarian Anarchism <br /><hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> sm3h0rl2lmq55vuhc1k54tsy6uz4a61 2408311 2408310 2022-07-21T05:55:13Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] [[File:Noam Chomsky signature.svg|thumb]] [[File:Chomsky-hierarchy.svg|thumb|Chomsky-hierarchy]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy * Socialist-Libertarian Anarchism <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 2005a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 1967a}} <hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> 0pzj3ijlqkkuzfghmmtocvvc6614xjg 2408320 2408311 2022-07-21T06:06:22Z Jtwsaddress42 234843 wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] [[File:Noam Chomsky signature.svg|thumb]] [[File:Chomsky-hierarchy.svg|thumb|Chomsky-hierarchy]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy * Socialist-Libertarian Anarchism <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 2005a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<br /><hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 1967a}} <hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> j2httz3aqsypms8kq5i4wgieaehb12i 2408321 2408320 2022-07-21T06:09:21Z Jtwsaddress42 234843 /* Chomsky, Noam (1929 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] [[File:Noam Chomsky signature.svg|thumb]] [[File:Chomsky-hierarchy.svg|thumb|Chomsky-hierarchy]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy * Socialist-Libertarian Anarchism <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 2005a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 1967a}} <hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> 79qu9lqn34iwokkue3imsto21jzd7hv 2408344 2408321 2022-07-21T06:37:20Z Jtwsaddress42 234843 /* Chomsky, Noam (1929 - ) */ wikitext text/x-wiki {{RoundBoxTop|theme=3}} === [[w:Noam Chomsky|Chomsky, Noam (1929 - )]] === <hr /> [[File:Noam Chomsky portrait 2017 retouched.png|thumb|Noam Chomsky 2017]] [[File:Noam Chomsky signature.svg|thumb]] [[File:Chomsky-hierarchy.svg|thumb|Chomsky-hierarchy]] '''Notable Accomplishments''' * Father of Modern Linguistics * Critique of Skinnerian Behaviorism * Critique of U.S. Foreign and Domestic Policy * Socialist-Libertarian Anarchism <br /><hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 2005a}} <hr /> '''Publications''' {{User:Jtwsaddress42/Bibliography/Chomsky, Noam}} <hr /> Buckley Jr. et al.<hr /> {{User:Jtwsaddress42/Bibliography/Buckley Jr. & Chomsky}} Hauser et al.<hr /> {{User:Jtwsaddress42/Bibliography/Hauser, Marc D.}} Herman et al.<hr /> {{User:Jtwsaddress42/Bibliography/Herman, Edward S.}} Lenneberg et al.<hr /> {{User:Jtwsaddress42/Bibliography/Lenneberg, Eric H.}} Stemmer et al.<hr /> {{User:Jtwsaddress42/Bibliography/Stemmer, Brigitte}} <hr /> {{User:Jtwsaddress42/Quotes/Chomsky, Noam 1967a}} <hr /> '''Related''' {{User:Jtwsaddress42/Bibliography/Barsky, Robert F.}} {{User:Jtwsaddress42/Bibliography/Calvin & Bickerton}} {{User:Jtwsaddress42/Bibliography/Collier, Peter}} {{RoundBoxBottom}} <hr /> 2x3fl070wqttkhzl34inbftngrpiktp 2 285526 2408281 2022-07-21T05:04:24Z Jtwsaddress42 234843 New resource with "* {{cite book | last= Barsky | first= Robert F. | year= 1996 | title= Noam Chomsky - A Life of Dissent | publisher= MIT Press | publication-date= 1997 | isbn= 978-0-262-02418-1 | url= https://www.google.com/books/edition/Noam_Chomsky/pZxSngEACAAJ?hl=en }}" wikitext text/x-wiki * {{cite book | last= Barsky | first= Robert F. | year= 1996 | title= Noam Chomsky - A Life of Dissent | publisher= MIT Press | publication-date= 1997 | isbn= 978-0-262-02418-1 | url= https://www.google.com/books/edition/Noam_Chomsky/pZxSngEACAAJ?hl=en }} c1ih9vt3lnqgqh2nmfqpuuic5r0lid4 2 285527 2408283 2022-07-21T05:07:50Z Jtwsaddress42 234843 New resource with "* {{cite AV media | last1= Buckley Jr. | first1= William F. | last2= Chomsky | first2= Noam | year= 1969 | title= Vietnam and the Intellectuals | series= Firing Line with William F. Buckley Jr. | medium= Episode 143, Recorded on April 3, 1969 | publisher= Hoover Institution Archives | publication-date= January 25, 2017 | url= https://www.youtube.com/watch?v=9DvmLMUfGss }} [[File:High-contrast-camera-video.svg|24px|video]] (0:52:11)" wikitext text/x-wiki * {{cite AV media | last1= Buckley Jr. | first1= William F. | last2= Chomsky | first2= Noam | year= 1969 | title= Vietnam and the Intellectuals | series= Firing Line with William F. Buckley Jr. | medium= Episode 143, Recorded on April 3, 1969 | publisher= Hoover Institution Archives | publication-date= January 25, 2017 | url= https://www.youtube.com/watch?v=9DvmLMUfGss }} [[File:High-contrast-camera-video.svg|24px|video]] (0:52:11) fqi17iqou1yvml7tn2aqvulgzo7iprb 2 285528 2408286 2022-07-21T05:11:01Z Jtwsaddress42 234843 New resource with "* {{cite book | last1= Calvin, William H.; Bickerton, Derek | year= 2000 | title= Lingua ex Machina: Reconciling Darwin and Chomsky With The Human Brain | publisher= A Bradford Book, MIT Press | isbn= 978-0-262-53198-6 | url= https://mitpress.mit.edu/books/lingua-ex-machina }}" wikitext text/x-wiki * {{cite book | last1= Calvin, William H.; Bickerton, Derek | year= 2000 | title= Lingua ex Machina: Reconciling Darwin and Chomsky With The Human Brain | publisher= A Bradford Book, MIT Press | isbn= 978-0-262-53198-6 | url= https://mitpress.mit.edu/books/lingua-ex-machina }} 80w1zabqp3o4rtx4qizqw77pjeu69mo 2 285529 2408288 2022-07-21T05:15:11Z Jtwsaddress42 234843 New resource with "*{{cite book | last1= Collier | first1= Peter (editor) | last2= Horowitz | first2= David (editor) | year= 2004 | title= The Anti-Chomsky Reader | publisher= Encounter Books | publication-date= September 25, 2004 | isbn= 978-1-893-55497-9 | url= https://www.google.com/books/edition/_/u7hoAAAAIAAJ?hl=en&sa=X&ved=2ahUKEwjM15-risT0AhVYKDQIHUEmAh0Q8fIDegQIBRAI }}" wikitext text/x-wiki *{{cite book | last1= Collier | first1= Peter (editor) | last2= Horowitz | first2= David (editor) | year= 2004 | title= The Anti-Chomsky Reader | publisher= Encounter Books | publication-date= September 25, 2004 | isbn= 978-1-893-55497-9 | url= https://www.google.com/books/edition/_/u7hoAAAAIAAJ?hl=en&sa=X&ved=2ahUKEwjM15-risT0AhVYKDQIHUEmAh0Q8fIDegQIBRAI }} ojmsbofuxvowhzrhcyvtl3t5752yuxo 2 285530 2408291 2022-07-21T05:19:41Z Jtwsaddress42 234843 New resource with "* {{cite journal | last1= Hauser | first1= Marc D. | last2= Yang | first2= Charles | last3= Berwick | first3= Robert C. | last4= Tattersal | first4= Ian | last5= Ryan | first5= Michael J. | last6= Watumull | first6= Jeffrey | last7= Chomsky | first7= Noam | last8= Lewontin | first8= Richard C. | year= 2014 | title= The mystery of language evolution | journal= Frontiers in Psychology | series= Language Sciences| volume= 5 | number= 401 | pages= eCollection 2014 | publica..." wikitext text/x-wiki * {{cite journal | last1= Hauser | first1= Marc D. | last2= Yang | first2= Charles | last3= Berwick | first3= Robert C. | last4= Tattersal | first4= Ian | last5= Ryan | first5= Michael J. | last6= Watumull | first6= Jeffrey | last7= Chomsky | first7= Noam | last8= Lewontin | first8= Richard C. | year= 2014 | title= The mystery of language evolution | journal= Frontiers in Psychology | series= Language Sciences| volume= 5 | number= 401 | pages= eCollection 2014 | publication-date= May 7, 2014 | pmid= 24847300 | pmc= 4019876 | doi= 10.3389/fpsyg.2014.00401 | url= https://www.frontiersin.org/articles/10.3389/fpsyg.2014.00401/full }} dzh0io18e8shd9nkdxmcyciikhntcc4 2408319 2408291 2022-07-21T06:05:07Z Jtwsaddress42 234843 wikitext text/x-wiki * {{cite journal | last1= Hauser | first1= Marc D. | last2= Yang | first2= Charles | last3= Berwick | first3= Robert C. | last4= Tattersal | first4= Ian | last5= Ryan | first5= Michael J. | last6= Watumull | first6= Jeffrey | last7= Chomsky | first7= Noam | last8= Lewontin | first8= Richard C. | year= 2014 | title= The mystery of language evolution | journal= Frontiers in Psychology | series= Language Sciences | volume= 5 | number= 401 | pages= eCollection 2014 | publication-date= May 7, 2014 | pmid= 24847300 | pmc= 4019876 | doi= 10.3389/fpsyg.2014.00401 | url= https://www.frontiersin.org/articles/10.3389/fpsyg.2014.00401/full }} l6z3k8st4rpfyypw3ru08totxpc5fk5 2 285531 2408293 2022-07-21T05:21:51Z Jtwsaddress42 234843 New resource with "* {{cite book | last1= Herman | first1= Edward S. | last2= Chomsky | first2= Noam | year= 1988 | title= Manufacturing Consent - The Political Economy of the Mass Media | publisher= Pantheon Books | isbn= 978-0-679-72034-8 | url= https://www.google.com/books/edition/_/kNRMngEACAAJ?hl=en&sa=X&ved=2ahUKEwislr3rocT0AhU8HDQIHS2aDnoQ8fIDegQIDBAM }}" wikitext text/x-wiki * {{cite book | last1= Herman | first1= Edward S. | last2= Chomsky | first2= Noam | year= 1988 | title= Manufacturing Consent - The Political Economy of the Mass Media | publisher= Pantheon Books | isbn= 978-0-679-72034-8 | url= https://www.google.com/books/edition/_/kNRMngEACAAJ?hl=en&sa=X&ved=2ahUKEwislr3rocT0AhU8HDQIHS2aDnoQ8fIDegQIDBAM }} dqzg91wd7jzg4h7m14oers65bzjdgg7 2 285532 2408299 2022-07-21T05:26:52Z Jtwsaddress42 234843 New resource with "* {{cite book | last1= Lenneberg | first1= Eric H. | last2= Chomsky | first2= Noam | last3= Marx | first3= Otto | year= 1967 | title= Biological Foundations Of Language | publisher= John Wiley & Sons | publication-date= January 15, 1967 | isbn= 978-0-471-52626-1 | url= https://www.google.com/books/edition/Biological_Foundations_of_Language/7UZiAAAAMAAJ?hl=en }}" wikitext text/x-wiki * {{cite book | last1= Lenneberg | first1= Eric H. | last2= Chomsky | first2= Noam | last3= Marx | first3= Otto | year= 1967 | title= Biological Foundations Of Language | publisher= John Wiley & Sons | publication-date= January 15, 1967 | isbn= 978-0-471-52626-1 | url= https://www.google.com/books/edition/Biological_Foundations_of_Language/7UZiAAAAMAAJ?hl=en }} mcr3sp02ipxlrc7b0wojs97s5f4d2du 2 285533 2408301 2022-07-21T05:29:17Z Buckminsterfullrene 2945188 I have a few interests, one of which is botany. I will contribute as much as I can to Bloom Clock's database. wikitext text/x-wiki Hi, I'll be adding as many as I can from Chennai, India 8qo3yn7d5klsw7ob9c7nujtccmzvn3w 2 285534 2408302 2022-07-21T05:32:13Z Jtwsaddress42 234843 New resource with "* {{cite journal | last1= Stemmer | first1= Brigitte | last2= Chomsky | first2= Noam | year= 1999 | title= An On-Line Interview with Noam Chomsky: On the Nature of Pragmatics and Related Issues | journal= Brain and Language | volume= 68 | pages= 393-401 | publication-date= 1999 | pmid= 10441185 | doi= 10.1006/brln.1999.2119 | url= https://www.sciencedirect.com/science/article/abs/pii/S0093934X99921193?via%3Dihub }}" wikitext text/x-wiki * {{cite journal | last1= Stemmer | first1= Brigitte | last2= Chomsky | first2= Noam | year= 1999 | title= An On-Line Interview with Noam Chomsky: On the Nature of Pragmatics and Related Issues | journal= Brain and Language | volume= 68 | pages= 393-401 | publication-date= 1999 | pmid= 10441185 | doi= 10.1006/brln.1999.2119 | url= https://www.sciencedirect.com/science/article/abs/pii/S0093934X99921193?via%3Dihub }} pjlr4h4spruahfalacrbmyitxrntjsx 2 285535 2408309 2022-07-21T05:41:46Z Congariel 2946865 Created blank page wikitext text/x-wiki phoiac9h4m842xq45sp7s6u21eteeq1 0 285536 2408316 2022-07-21T05:58:58Z Congariel 2946865 New resource with "{{Center|{{huge|'''ꠍꠤꠟꠐꠤ'''}}<br>{{big|'''''Silôṭi maṭ'''''}}<br>{{big|''Syloti language''}}}} {{languages}} {{lesson}} {{51%done-2}} This course is intended to teach the '''{{w|Syloti language}}'''. == Who is this course for? == This is a comprehensive course for people who want to develop linguistic (lexical, grammatical and phonetic) and communication skills in the Sylheti language. ==First contact== Let's dive straight into some simple Sylheti sente..." wikitext text/x-wiki {{Center|{{huge|'''ꠍꠤꠟꠐꠤ'''}}<br>{{big|'''''Silôṭi maṭ'''''}}<br>{{big|''Syloti language''}}}} {{languages}} {{lesson}} {{51%done-2}} This course is intended to teach the '''{{w|Syloti language}}'''. == Who is this course for? == This is a comprehensive course for people who want to develop linguistic (lexical, grammatical and phonetic) and communication skills in the Sylheti language. ==First contact== Let's dive straight into some simple Sylheti sentences to give you a first impression of how Sylheti is structured. Sentence 1 : I speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি<br> si•lo•ṭi !! মাতি <br> ma•ti |- | I || Syloti || speak. |- | Subject || Direct Object || Verb |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> le = লে <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি |} Note : The simple affirmative present tense Syloti sentence follows the Subject-Object-Verb (SOV) word order. Sentence 2 : I do not speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি <br> si•lo•ṭi !! মাতি <br> ma•ti !! না <br> naa. |- | I || Syloti || speak || not |- | Subject || Direct Object || Verb || Negative marker for present |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> lo = ল <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি || n = ন <br> na = না |} Note : The simple negative present tense Sylheti sentence adds the negative marker -naa after the verb to make it negative. Note : 1. As the subject changes from ami (I) to tumi (You), observe that the form of the present tense verb changes. To learn more about this, see [[/Verbs/]] == List of Grammar Lessons (not in order) == * Lesson x. [[/Pronouns/]] * Lesson x. [[/Nouns/]] * Lesson x. [[/Verbs/]] * Lesson x. [[/Adjectives/]] * Lesson x. [[/Adverbs/]] * Lesson x. [[/Degree Modifiers for adjectives, adverbs and verbs/]] * Lesson x. [[/Comparison with nouns, adjectives, adverbs and verbs/]] * Lesson x. [[/Object Pronouns/]] * Lesson x. [[/Word Order/]] * Lesson x. [[/Postpositions/]] * Lesson x. [[/Expressing temporal information/]] ('''When''' or '''how often''' something happens) * Lesson x. [[/Expressing locative information/]] ('''Where''' something happens) * Lesson x. [[/Expressing Obligation with Verb/]] (modal auxiliary "zoruri") * Lesson x. [[/Expressing Possibility with Verb/]] (modal auxiliary "fara") * Lesson x. [[/Expressing Ability or Knowhow with Verb/]] (modal auxiliary "zana" or "fara") * Lesson x. [[/Expressing Want with Verb/]] (modal auxiliary "saua") * Lesson x. [[/Expressing Need with Verb/]] (modal auxiliary "dorkhar" or "laga") * Lesson x. [[/Expressing Cause/]] ('''Why''' something happens) * Lesson x. [[/Expressing Consequence/]] * Lesson x. [[/Expressing Goal/]] ('''For what''' something happens) * Lesson x. [[/Expressing Opposition/]] (how to say ''but, on the contrary, however,'' etc.) * Lesson x. [[/Expressing Addition of Ideas/]] (how to say ''and, moreover,'' etc) * Lesson x. [[/Expressing Conditions/]] (how to say ''if, unless, depends'' etc) * Lesson x. [[/Expressing Anteriority, Posteriority and Simultaneity/]] (how to say ''before, after, during'' etc) * Lesson x. [[/Characterizing using relative clauses/]] (how to add information using ''who, which, where, whose, that'' etc) * Lesson x. [[/Asking Questions/]] ==List of Vocabulary Lessons (not in order)== * Lesson x. [[/Greetings and basic polite expressions/]] * Lesson x. [[/Numbers/]] * Lesson x. [[/Measurements and Quantities/]] * Lesson x. [[/Characteristics of Objects/]]: Size, Shape, Material, Texture, Color * Lesson x. [[/Geography and nationalities/]] * Lesson x. [[/Languages/]] * Lesson x. [[/Human Body/]] * Lesson x. [[/Movements, Gestures and Postures/]] * Lesson x. [[/Cycle of Life/]] * Lesson x. [[/Family/]] * Lesson x. [[/Relationships/]] * Lesson x. [[/Personal Information/]] * Lesson x. [[/Daily activities/]] * Lesson x. [[/Housing/]] * Lesson x. [[/Appearance and Clothing/]] * Lesson x. [[/Places in the city/]] * Lesson x. [[/Directions/]] * Lesson x. [[/Traveling, roads and transport/]] * Lesson x. [[/Personal Objects/]] * Lesson x. [[/Education/]] * Lesson x. [[/Work and Workplaces/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Vacation/]] * Lesson x. [[/Leisure activities/]] * Lesson x. [[/Animals/]] * Lesson x. [[/Plants and Trees/]] * Lesson x. [[/Food/]] * Lesson x. [[/Eating out/]] * Lesson x. [[/Cooking, Recipes and Gastronomy/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Graphic Arts/]] * Lesson x. [[/Theater/]] * Lesson x. [[/Cinema/]] * Lesson x. [[/Music/]] * Lesson x. [[/Architecture/]] * Lesson x. [[/Photography/]] * Lesson x. [[/Sports and games/]] * Lesson x. [[/Post office and other services/]] * Lesson x. [[/Media/]] * Lesson x. [[/Computers and Internet/]] * Lesson x. [[/Books and literature/]] * Lesson x. [[/Intellectual life/]] * Lesson x. [[/Communication/]] * Lesson x. [[/Feelings and Emotions/]] * Lesson x. [[/Health and Medicine/]] * Lesson x. [[/Fashion/]] * Lesson x. [[/Money and Banking/]] * Lesson x. [[/Character and Personality/]] * Lesson x. [[/Science and Research/]] * Lesson x. [[/Crime, Law and Justice/]] * Lesson x. [[/Environment/]] * Lesson x. [[/Weather and Climate/]] * Lesson x. [[/Economy and Finances/]] * Lesson x. [[/Politics/]] * Lesson x. [[/Social Issues/]] * Lesson x. [[/Morality/]] * Lesson x. [[/Mind and psychology/]] * Lesson x. [[/Time/]] * Lesson x. [[/The Past/]] * Lesson x. [[/The Future/]] * Lesson x. [[/Belief and religion/]] ==Appendices== * Appendix x. [[/Foreign words/]] [[Category:Sylheti language]] 2q8ov0nj3vjmdssju5iedbg716lbwpd 2408317 2408316 2022-07-21T06:00:05Z Congariel 2946865 Sylheti language in Wikipedia wikitext text/x-wiki {{Center|{{huge|'''ꠍꠤꠟꠐꠤ'''}}<br>{{big|'''''Silôṭi maṭ'''''}}<br>{{big|''Syloti language''}}}} {{languages}} {{lesson}} {{51%done-2}} This course is intended to teach the '''{{w|Sylheti language}}'''. == Who is this course for? == This is a comprehensive course for people who want to develop linguistic (lexical, grammatical and phonetic) and communication skills in the Sylheti language. ==First contact== Let's dive straight into some simple Sylheti sentences to give you a first impression of how Sylheti is structured. Sentence 1 : I speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি<br> si•lo•ṭi !! মাতি <br> ma•ti |- | I || Syloti || speak. |- | Subject || Direct Object || Verb |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> le = লে <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি |} Note : The simple affirmative present tense Syloti sentence follows the Subject-Object-Verb (SOV) word order. Sentence 2 : I do not speak Syloti. {| class="wikitable" |- ! আমি <br> a•mi !! সিলটি <br> si•lo•ṭi !! মাতি <br> ma•ti !! না <br> naa. |- | I || Syloti || speak || not |- | Subject || Direct Object || Verb || Negative marker for present |- | a = আ <br> m = ম <br> mi = মি<br> Ami = আমি<br> || s = স<br> si = সি<br> l = ল <br> lo = ল <br> ṭ = ট <br> ṭi = টি <br> siloti = সিলটি<br> || m = ম <br> ma = মা <br> t = ত <br> ti = তি <br> mati = মাতি || n = ন <br> na = না |} Note : The simple negative present tense Sylheti sentence adds the negative marker -naa after the verb to make it negative. Note : 1. As the subject changes from ami (I) to tumi (You), observe that the form of the present tense verb changes. To learn more about this, see [[/Verbs/]] == List of Grammar Lessons (not in order) == * Lesson x. [[/Pronouns/]] * Lesson x. [[/Nouns/]] * Lesson x. [[/Verbs/]] * Lesson x. [[/Adjectives/]] * Lesson x. [[/Adverbs/]] * Lesson x. [[/Degree Modifiers for adjectives, adverbs and verbs/]] * Lesson x. [[/Comparison with nouns, adjectives, adverbs and verbs/]] * Lesson x. [[/Object Pronouns/]] * Lesson x. [[/Word Order/]] * Lesson x. [[/Postpositions/]] * Lesson x. [[/Expressing temporal information/]] ('''When''' or '''how often''' something happens) * Lesson x. [[/Expressing locative information/]] ('''Where''' something happens) * Lesson x. [[/Expressing Obligation with Verb/]] (modal auxiliary "zoruri") * Lesson x. [[/Expressing Possibility with Verb/]] (modal auxiliary "fara") * Lesson x. [[/Expressing Ability or Knowhow with Verb/]] (modal auxiliary "zana" or "fara") * Lesson x. [[/Expressing Want with Verb/]] (modal auxiliary "saua") * Lesson x. [[/Expressing Need with Verb/]] (modal auxiliary "dorkhar" or "laga") * Lesson x. [[/Expressing Cause/]] ('''Why''' something happens) * Lesson x. [[/Expressing Consequence/]] * Lesson x. [[/Expressing Goal/]] ('''For what''' something happens) * Lesson x. [[/Expressing Opposition/]] (how to say ''but, on the contrary, however,'' etc.) * Lesson x. [[/Expressing Addition of Ideas/]] (how to say ''and, moreover,'' etc) * Lesson x. [[/Expressing Conditions/]] (how to say ''if, unless, depends'' etc) * Lesson x. [[/Expressing Anteriority, Posteriority and Simultaneity/]] (how to say ''before, after, during'' etc) * Lesson x. [[/Characterizing using relative clauses/]] (how to add information using ''who, which, where, whose, that'' etc) * Lesson x. [[/Asking Questions/]] ==List of Vocabulary Lessons (not in order)== * Lesson x. [[/Greetings and basic polite expressions/]] * Lesson x. [[/Numbers/]] * Lesson x. [[/Measurements and Quantities/]] * Lesson x. [[/Characteristics of Objects/]]: Size, Shape, Material, Texture, Color * Lesson x. [[/Geography and nationalities/]] * Lesson x. [[/Languages/]] * Lesson x. [[/Human Body/]] * Lesson x. [[/Movements, Gestures and Postures/]] * Lesson x. [[/Cycle of Life/]] * Lesson x. [[/Family/]] * Lesson x. [[/Relationships/]] * Lesson x. [[/Personal Information/]] * Lesson x. [[/Daily activities/]] * Lesson x. [[/Housing/]] * Lesson x. [[/Appearance and Clothing/]] * Lesson x. [[/Places in the city/]] * Lesson x. [[/Directions/]] * Lesson x. [[/Traveling, roads and transport/]] * Lesson x. [[/Personal Objects/]] * Lesson x. [[/Education/]] * Lesson x. [[/Work and Workplaces/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Vacation/]] * Lesson x. [[/Leisure activities/]] * Lesson x. [[/Animals/]] * Lesson x. [[/Plants and Trees/]] * Lesson x. [[/Food/]] * Lesson x. [[/Eating out/]] * Lesson x. [[/Cooking, Recipes and Gastronomy/]] * Lesson x. [[/Shops and shopping/]] * Lesson x. [[/Graphic Arts/]] * Lesson x. [[/Theater/]] * Lesson x. [[/Cinema/]] * Lesson x. [[/Music/]] * Lesson x. [[/Architecture/]] * Lesson x. [[/Photography/]] * Lesson x. [[/Sports and games/]] * Lesson x. [[/Post office and other services/]] * Lesson x. [[/Media/]] * Lesson x. [[/Computers and Internet/]] * Lesson x. [[/Books and literature/]] * Lesson x. [[/Intellectual life/]] * Lesson x. [[/Communication/]] * Lesson x. [[/Feelings and Emotions/]] * Lesson x. [[/Health and Medicine/]] * Lesson x. [[/Fashion/]] * Lesson x. [[/Money and Banking/]] * Lesson x. [[/Character and Personality/]] * Lesson x. [[/Science and Research/]] * Lesson x. [[/Crime, Law and Justice/]] * Lesson x. [[/Environment/]] * Lesson x. [[/Weather and Climate/]] * Lesson x. [[/Economy and Finances/]] * Lesson x. [[/Politics/]] * Lesson x. [[/Social Issues/]] * Lesson x. [[/Morality/]] * Lesson x. [[/Mind and psychology/]] * Lesson x. [[/Time/]] * Lesson x. [[/The Past/]] * Lesson x. [[/The Future/]] * Lesson x. [[/Belief and religion/]] ==Appendices== * Appendix x. [[/Foreign words/]] [[Category:Sylheti language]] gtpc28ob7dpxwo1y7py5dbutxihxk1d 2 285537 2408396 2022-07-21T11:47:44Z Ramiindadoo 2946875 added contant wikitext text/x-wiki My user page bihc1fzrlzpm5gykv3rg4nfu0sodl1c 3 285538 2408397 2022-07-21T11:48:23Z Ramiindadoo 2946875 Fixed wikitext text/x-wiki My user page bihc1fzrlzpm5gykv3rg4nfu0sodl1c 2408398 2408397 2022-07-21T11:48:51Z Ramiindadoo 2946875 /* User */ new section wikitext text/x-wiki My user page == User == My user [[User:Ramiindadoo|Ramiindadoo]] ([[User talk:Ramiindadoo|discuss]] • [[Special:Contributions/Ramiindadoo|contribs]]) 11:48, 21 July 2022 (UTC) d4bximiz85p3mssn8iajp695khnbdkz